Structural highlights
Disease
[TRPC3_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[TRPC3_HUMAN] Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C, and by inositol 1,4,5-triphosphate receptors (ITPR) with bound IP3. May also be activated by internal calcium store depletion.[1] [2] [3] [4]
Publication Abstract from PubMed
The transient receptor potential ion channels support Ca(2+) permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8 and 4.0 A resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD, where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.
Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating.,Sierra-Valdez F, Azumaya CM, Romero LO, Nakagawa T, Cordero-Morales JF J Biol Chem. 2018 Aug 23. pii: RA118.005066. doi: 10.1074/jbc.RA118.005066. PMID:30139744[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Woo JS, Hwang JH, Ko JK, Weisleder N, Kim DH, Ma J, Lee EH. S165F mutation of junctophilin 2 affects Ca2+ signalling in skeletal muscle. Biochem J. 2010 Mar 15;427(1):125-34. doi: 10.1042/BJ20091225. PMID:20095964 doi:https://dx.doi.org/10.1042/BJ20091225
- ↑ Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell. 1996 May 31;85(5):661-71. PMID:8646775
- ↑ Zhu X, Jiang M, Birnbaumer L. Receptor-activated Ca2+ influx via human Trp3 stably expressed in human embryonic kidney (HEK)293 cells. Evidence for a non-capacitative Ca2+ entry. J Biol Chem. 1998 Jan 2;273(1):133-42. PMID:9417057
- ↑ Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999 Jan 21;397(6716):259-63. doi: 10.1038/16711. PMID:9930701 doi:https://dx.doi.org/10.1038/16711
- ↑ Sierra-Valdez F, Azumaya CM, Romero LO, Nakagawa T, Cordero-Morales JF. Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating. J Biol Chem. 2018 Aug 23. pii: RA118.005066. doi: 10.1074/jbc.RA118.005066. PMID:30139744 doi:https://dx.doi.org/10.1074/jbc.RA118.005066
