Proteopedia - User contributions [en]

Short transient receptor potential channel

2025-11-30T18:24:27Z

Mari Debbarma: final changes

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

[[Image:Asymmetry_(TRPC1_TRPC4_Stoichiometry)_.png]]
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

[[Image:Selectivity_Filter_Narrowing_(L601)_.png]]

3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
[[Image:Calcium_Permeability_(K639_in_S6)_.png]]

</StructureSection>
== References ==
<references/>

Short transient receptor potential channel

2025-11-30T18:23:29Z

Mari Debbarma: added the rest of the images

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>[[Image:Asymmetry_(TRPC1_TRPC4_Stoichiometry)_.png]]
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>[[Image:Selectivity_Filter_Narrowing_(L601)_.png]]
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>[[Image:Calcium_Permeability_(K639_in_S6)_.png]]

</StructureSection>
== References ==
<references/>

File:Calcium Permeability (K639 in S6) .png

2025-11-30T18:21:17Z

Mari Debbarma: The positively charged K639 from TRPC1 creates an electropositive environment deep in the pore that repels positively charged $\text{Ca}^{2+}$ ions

The positively charged K639 from TRPC1 creates an electropositive environment deep in the pore that repels positively charged $\text{Ca}^{2+}$ ions

File:Selectivity Filter Narrowing (L601) .png

2025-11-30T18:19:37Z

Mari Debbarma: L601 (TRPC1) physically projects into the pore, driven by a longer selectivity filter loop, narrowing the ion pathway and altering monovalent ion preference.

L601 (TRPC1) physically projects into the pore, driven by a longer selectivity filter loop, narrowing the ion pathway and altering monovalent ion preference.

Short transient receptor potential channel

2025-11-30T18:17:49Z

Mari Debbarma: changed the picture again, as the initial one failed

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway.[[Image:Asymmetry_(TRPC1_TRPC4_Stoichiometry)_.png]] <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

</StructureSection>
== References ==
<references/>

Short transient receptor potential channel

2025-11-30T18:13:36Z

Mari Debbarma: added a png in structures

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway.[[File:Asymmetry_(TRPC1_TRPC4_Stoichiometry)_.png|thumb|400px|The heterotetrameric structure, composed of one TRPC1 subunit and three TRPC4 subunits, breaks the channel's 4-fold symmetry, creating an asymmetric ion-conduction pathway.]] <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

</StructureSection>
== References ==
<references/>

File:Asymmetry (TRPC1 TRPC4 Stoichiometry) .png

2025-11-30T18:10:08Z

Mari Debbarma: TRPC1 changing the symmetry when incorporated in TRPC4

TRPC1 changing the symmetry when incorporated in TRPC4

Short transient receptor potential channel

2025-11-30T18:02:02Z

Mari Debbarma: removed the codes

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

</StructureSection>
== References ==
<references/>

File:Calcium Permeability (K639 in S6).pse

2025-11-30T17:56:06Z

Mari Debbarma: $\text{K639}$ on TRPC1 acts as an electrostatic barrier that actively excludes $\text{Ca}^{2+}$ from the central conduction pathway

$\text{K639}$ on TRPC1 acts as an electrostatic barrier that actively excludes $\text{Ca}^{2+}$ from the central conduction pathway

File:Selectivity Filter Narrowing (L601).pse

2025-11-30T17:54:06Z

Mari Debbarma: The extra length of the TRPC1 loop, anchored by the protruding $\text{L601}$ side chain, creates an asymmetric constriction in the selectivity filter, which is the mechanism behind the channel's shift toward monovalent ion selectivity

The extra length of the TRPC1 loop, anchored by the protruding $\text{L601}$ side chain, creates an asymmetric constriction in the selectivity filter, which is the mechanism behind the channel's shift toward monovalent ion selectivity

File:1. Asymmetry (TRPC1 TRPC4 Stoichiometry).pse

2025-11-30T17:52:11Z

Mari Debbarma: The incorporation of the single TRPC1 subunit is the structural determinant that converts a symmetric pore into an asymmetric one, thereby changing its function

The incorporation of the single TRPC1 subunit is the structural determinant that converts a symmetric pore into an asymmetric one, thereby changing its function

Short transient receptor potential channel

2025-11-30T14:18:05Z

Mari Debbarma: new codes for the images, manual

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

=== Figure 1: Asymmetric Tetramer Assembly (1:3 Stoichiometry) ===
The TRPC1/TRPC4 channel structure (PDB 8WPL) displays an overall asymmetric tetrameric assembly, consisting of one TRPC1 subunit (Chain D) and three TRPC4 subunits (Chains A, B, C). This configuration breaks the expected C4 symmetry.
<StructureSection load='8WPL' size='340' side='right' caption='Figure 1: Overall Asymmetric Assembly of TRPC1/TRPC4 (1:3)' Commands='select all; cartoon; color chain; zoom 100; orient 0 0 0 1 0;'>
</StructureSection>
=== Figure 2: The K639 Calcium Gate ===
Calcium permeability is dictated by the **K639 residue** on the TRPC1 subunit. This residue protrudes into the central cavity, where its positive charge repels positively charged calcium ions, providing the mechanism for reduced calcium influx.
<StructureSection load='8WPL' size='340' side='right' caption='Figure 2: K639 residue (red) controlling the central cavity' Commands='select all; cartoon; color cartoon chain; select :639.D; wireframe off; spacefill 0.6; color red, :639.D; zoom 150;'>
</StructureSection>
=== Figure 3: The L601 Selectivity Filter ===
The channel's selectivity for monovalent ions is determined by the **L601 residue** on TRPC1. This residue causes a physical constriction at the selectivity filter, narrowing the pore radius and affecting ion preference.
<StructureSection load='8WPL' size='340' side='right' caption='Figure 3: L601 residue (magenta) constricting the selectivity filter' Commands='select all; cartoon; color cartoon chain; select :601.D; wireframe 0.2; color magenta, :601.D; zoom 200; orient 0 0 0 1 0;'>
</StructureSection>
</StructureSection>
== References ==
<references/>

Short transient receptor potential channel

2025-11-30T14:12:28Z

Mari Debbarma: changed 3D picture codes

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

=== Figure 1: Asymmetric Tetramer Assembly (1:3 Stoichiometry) ===
The TRPC1/TRPC4 channel structure (PDB 8WPL) displays an overall asymmetric tetrameric assembly, consisting of one TRPC1 subunit (Chain D) and three TRPC4 subunits (Chains A, B, C). This configuration breaks the expected C4 symmetry.
<StructureSection load='8WPL' size='340' side='right' caption='Figure 1: Overall Asymmetric Assembly of TRPC1/TRPC4 (1:3)' Commands='select all; color chain; zoom 100; orient center'>
</StructureSection>

=== Figure 2: The K639 Calcium Gate ===
Calcium permeability is dictated by the **K639 residue** on the TRPC1 subunit. This residue protrudes into the central cavity, where its positive charge repels positively charged calcium ions, providing the mechanism for reduced calcium influx.
<StructureSection load='8WPL' size='340' side='right' caption='Figure 2: K639 residue (red) controlling the central cavity' Commands='select all; spacefill off; backbone off; cartoon; color cartoon chain; select :639.D; wireframe off; spacefill 0.5; color red, :639.D; zoom 100'>
</StructureSection>

=== Figure 3: The L601 Selectivity Filter ===
The channel's selectivity for monovalent ions is determined by the **L601 residue** on TRPC1. This residue causes a physical constriction at the selectivity filter, narrowing the pore radius and affecting ion preference.
<StructureSection load='8WPL' size='340' side='right' caption='Figure 3: L601 residue (magenta) constricting the selectivity filter' Commands='select all; spacefill off; backbone off; cartoon; color cartoon chain; select :601.D; wireframe 0.2; color magenta, :601.D; zoom 100'>
</StructureSection>

</StructureSection>
== References ==
<references/>

Short transient receptor potential channel

2025-11-30T14:06:10Z

Mari Debbarma:

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway.{{Scene|PDB=8WPL|Scene=Asymmetric_Tetramer|Text=asymmetric ion-conduction pathway|Commands=select all; color chain; zoom; orient center}} <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.{{Scene|PDB=8WPL|Scene=L601_Select_Filter|Text=L601 residue in the selectivity filter|Commands=select all; spacefill off; backbone off; cartoon; color cartoon chain; select :601.D; wireframe 0.2; color magenta, :601.D; zoom; orient center}}
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged.{{Scene|PDB=8WPL|Scene=K639_Ca_Gate|Text=K639 residue here|Commands=select all; spacefill off; backbone off; cartoon; color cartoon chain; select :639.D; wireframe off; spacefill 0.5; color red, :639.D}} <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

</StructureSection>
== References ==
<references/>

Short transient receptor potential channel

2025-11-30T13:55:10Z

Mari Debbarma: structures highlight and 3D pictures included

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This paper shows the detailed 3D structure of the human TRPC1-TRPC4 ion channel. This channel is made of one TRPC1 nd three TRPC4 subunits. The researchers captured(using cro-Electron Microscopy) what the channel looks like normally and when blocked by a drug, Pico145. <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Main finding: The incorporation of one TRPC1 completely changes the shape of the TRPC4 channel. It changes TRPC4 from a perfectly symmetrical pore to an asymmetric heteromer(TRPC1/TRPC4). This asymmetry narrows the ion pathway, bends several helices, and creates a different lower gate. This decreases the calcium permeability and shifts the preference to monovalent ions such as sodium and potassium. Electrical tests and mutant experiments confirm that this structural shift affects how the channel actually works.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
The structure in this paper also shows why the drug Pico145 binds tightly. This is because TRPC1 provides extra hydrophobic residues( F575 and F592) that form a tighter drug-binding pocket, which makes Pico145 more effective on TRPC1/TRPC4 channels compared to TRPC-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
Overall, these structural insights

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease == 1. Darier's disease, which is a genetic disorder, is caused by a mutation in SERCA2, the pump that stores calcium inside the endoplasmic reticulum. This inhibits Calcium flow inside, causing upregulation of TRPC1 to allow more calcium to enter. However, this activates NF-kB survival pathway, resists cell death, and pushes them towards overgrowth or abnormal keratinization.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2. TRPC4 helps stabilize the dendritic branches. Without TRPC4, brain circuits form incorrectly and cause neurodevelopmental effects.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037122.</ref>

== Relevance ==1. The asymmetric structure of TRPC1:TRPC4 creates a distinct identity compared to TRPC4 homomers. This would help Pharmaceutical scientists to develop drugs that specifically target the TRPC1/TRPC4 heteromer without affecting TRPC4 or other TRP family channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The structure shows how the antagonist Pico145 binds to the channel, creating a stronger hydrophobic interaction than TRPC4-only channels.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This can explain why Pico145 is more potent against TRPC1-containing channels or how drug binding is influenced by heteromer composition. This information can improve selectivity and reduce side effects.
3. Residues in TRPC1, such as L601(selectivity filter) and K639(in the central cavity), explains how TRPC1 alters TRPC4's functions.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>. This helps us understand how ion permeability leads to diseases.

== Structural highlights ==1. The channel, when TRPC1 is incorporated, loses the 4-fold symmetry with one TRPC1 and three TRPC4. This change in arrangement breaks the symmetry of the pore and creates a different, asymmetric ion-conduction pathway.{{Scene|PDB=8WPL|Scene=Asymmetric_Tetramer|Text=asymmetric 1:3 stoichiometry|Commands=select all; color chain; zoom; orient center}} <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
2. The selectivity filter loop(two maino acids longer than the corresponding loop in TRPC4) causes the loop to protrude further into the pore. L601 from TRPC1 is the key residue responsible for this, as it physically projects into the ion pathway, narrowing the pore radius. These change the channels' preference for monovalent channels.{{Scene|PDB=8WPL|Scene=L601_Select_Filter|Text=L601 residue in the selectivity filter|Commands=select all; spacefill off; backbone off; cartoon; color cartoon chain; select :601.D; wireframe 0.2; color magenta, :601.D; zoom; orient center}}
<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. Calcium permeability is determined by the S6 helix present depeer in the pore. The TRPC1 subunit provides K639 here, which carries a positive charge in the central cavity of the pore. This creates an electropositive environment repelling calcium, which is also positively charged.{{Scene|PDB=8WPL|Scene=K639_Ca_Gate|Text=K639 residue here|Commands=select all; spacefill off; backbone off; cartoon; color cartoon chain; select :639.D; wireframe off; spacefill 0.5; color red, :639.D}} <ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>

</StructureSection>
== References ==
<references/>

Sandbox TRPC1 TRPC4 8WPL

2025-11-30T12:39:15Z

Mari Debbarma: Sandbox TRPC1 TRPC4 8WPL moved to TRPC1 TRPC4 8WPL BI3323 Aug2025

#REDIRECT [[TRPC1 TRPC4 8WPL BI3323 Aug2025]]

Short transient receptor potential channel

2025-11-30T12:39:15Z

Mari Debbarma: Sandbox TRPC1 TRPC4 8WPL moved to TRPC1 TRPC4 8WPL BI3323 Aug2025

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This is a default text for your page '''Sandbox TRPC1 TRPC4 8WPL'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease ==

== Relevance ==

== Structural highlights ==

</StructureSection>
== References ==
<references/>

Short transient receptor potential channel

2025-11-29T01:39:36Z

Mari Debbarma: Initial page creation for Sandbox_TRPC1_TRPC4_8PWL

==Overview of the TRPC1/TRPC4 Channel==
<StructureSection load='8WPL' size='340' side='right' caption='Cryo-EM structure of the heteromeric human TRPC1/TRPC4 channel (PDB: 8WPL)' scene=''>
This is a default text for your page '''Sandbox TRPC1 TRPC4 8WPL'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Function == 1.TRCP1 helps the cell to fill up for SERCA2 deficiency so that the cell can survive by letting more calcium enter the endoplasmic reticulum. This activates survival pathways, such as NF-kB, reduces cell death, and promotes cell growth.<ref>Pani, B., Cornatzer, E. et al. (2006). Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease. ''Molecular Biology of the Cell'', 17(10):4446–4458.</ref>
2) when TRPC1 joins TRPC4 channel (1 TRPC1 and TRPC4) it pushes away Ca²⁺ as TRPC1 has an aminio acid(K639) which is positively charged pushing the positively charged calcium. It also develops more preference for Na⁺/K⁺ over Ca²⁺, while increasing inhibitor sensitivity.<ref>Won, J., Kim, J., Kim, J. et al. (2025). Cryo-EM structure of the heteromeric TRPC1/TRPC4 channel. ''Nature Structural & Molecular Biology'', 32(2):326–338. DOI: 10.1038/s41594-024-01408-1</ref>
3. TRPC4 is essential during early postnatal brain development, as it helps dendrites grow and stay stable by turning glutamate signals into calcium entry, activating a force-generating pathway. Without TRPC4, dendrites will disintegrate.<ref>Jeon, J., Moore, T. I., Sob, I. et al. (2025). TRPC4 regulates limbic behavior and neuronal development by stabilizing dendrite branches through actomyosin-driven integrin activation. ''PNAS'', 122(33):e2511037ca122.</ref>
== Disease ==

== Relevance ==

== Structural highlights ==

</StructureSection>
== References ==
<references/>