| Structural highlights
Function
CAHM1_HUMAN Pore-forming subunit of gustatory voltage-gated ion channels required for sensory perception of sweet, bitter and umami tastes (By similarity). With CALHM3 forms a fast-activating voltage-gated ATP-release channel in type II taste bud cells, ATP acting as a neurotransmitter to activate afferent neural gustatory pathways (By similarity) (PubMed:23467090). Acts both as a voltage-gated and calcium-activated ion channel: mediates neuronal excitability in response to membrane depolarization and low extracellular Ca(2+) concentration (PubMed:22711817, PubMed:23300080). Has poor ion selectivity and forms a wide pore (around 14 Angstroms) that mediates permeation of small ions including Ca(2+), Na(+), K(+) and Cl(-), as well as larger ions such as ATP(4-) (PubMed:22711817, PubMed:23300080, PubMed:32832629, PubMed:37380652). Mediates Ca(2+) influx and downstream activation of the ERK1 and ERK2 cascade in neurons (PubMed:23345406). Triggers endoplasmic reticulum stress by reducing the Ca(2+) content of the endoplasmic reticulum (PubMed:21574960). May indirectly control amyloid precursor protein (APP) proteolysis and aggregated amyloid-beta (Abeta) peptides levels in a Ca(2+)-dependent manner (PubMed:18585350).[UniProtKB:D3Z291][1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Calcium homeostasis modulator 1 (CALHM1) is a voltage-dependent channel involved in neuromodulation and gustatory signaling. Despite recent progress in the structural biology of CALHM1, insights into functional regulation, pore architecture, and channel blockade remain limited. Here we present the cryo-EM structure of human CALHM1, revealing an octameric assembly pattern similar to the non-mammalian CALHM1s and the lipid-binding pocket conserved across species. We demonstrate by MD simulations that this pocket preferentially binds a phospholipid over cholesterol to stabilize its structure and regulate the channel activities. Finally, we show that residues in the amino-terminal helix form the channel pore that ruthenium red binds and blocks.
Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red.,Syrjanen JL, Epstein M, Gomez R, Furukawa H Nat Commun. 2023 Jun 28;14(1):3821. doi: 10.1038/s41467-023-39388-3. PMID:37380652[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008 Jun 27;133(7):1149-61. PMID:18585350 doi:10.1016/j.cell.2008.05.048
- ↑ Gallego-Sandín S, Alonso MT, García-Sancho J. Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress. Biochem J. 2011 Aug 1;437(3):469-75. PMID:21574960 doi:10.1042/BJ20110479
- ↑ Ma Z, Siebert AP, Cheung KH, Lee RJ, Johnson B, Cohen AS, Vingtdeux V, Marambaud P, Foskett JK. Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):E1963-71. PMID:22711817 doi:10.1073/pnas.1204023109
- ↑ Siebert AP, Ma Z, Grevet JD, Demuro A, Parker I, Foskett JK. Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins, and innexins. J Biol Chem. 2013 Mar 1;288(9):6140-53. PMID:23300080 doi:10.1074/jbc.M112.409789
- ↑ Dreses-Werringloer U, Vingtdeux V, Zhao H, Chandakkar P, Davies P, Marambaud P. CALHM1 controls the Ca²⁺-dependent MEK, ERK, RSK and MSK signaling cascade in neurons. J Cell Sci. 2013 Mar 1;126(Pt 5):1199-206. PMID:23345406 doi:10.1242/jcs.117135
- ↑ Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A, Adrien L, Zhao H, Leung S, Abernethy M, Koppel J, Davies P, Civan MM, Chaudhari N, Matsumoto I, Hellekant G, Tordoff MG, Marambaud P, Foskett JK. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature. 2013 Mar 14;495(7440):223-6. PMID:23467090 doi:10.1038/nature11906
- ↑ Demura K, Kusakizako T, Shihoya W, Hiraizumi M, Nomura K, Shimada H, Yamashita K, Nishizawa T, Taruno A, Nureki O. Cryo-EM structures of calcium homeostasis modulator channels in diverse oligomeric assemblies. Sci Adv. 2020 Jul 17;6(29):eaba8105. doi: 10.1126/sciadv.aba8105. eCollection, 2020 Jul. PMID:32832629 doi:http://dx.doi.org/10.1126/sciadv.aba8105
- ↑ Syrjänen JL, Epstein M, Gómez R, Furukawa H. Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red. Nat Commun. 2023 Jun 28;14(1):3821. PMID:37380652 doi:10.1038/s41467-023-39388-3
- ↑ Syrjänen JL, Epstein M, Gómez R, Furukawa H. Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red. Nat Commun. 2023 Jun 28;14(1):3821. PMID:37380652 doi:10.1038/s41467-023-39388-3
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