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1.A.4.1.4
TRPC3 store-operated non-selective cation channel (activated by thapsigargin and 2 acyl glycerol; forms a heteromeric channel with TrpC1, TC #1.A.4.1.3) (Liu et al., 2005).  A  structural model of the TRPC3 permeation pathway based on a sodium channel (TC# 1.A.1.14.5) with a localized selectivity filter and an occluding gate with evidence for allosteric coupling between the gate and the selectivity filter has been proposed (Ko et al. 2009; Lichtenegger et al. 2013). The channel may have a large internal chamber surrounded by signal sensing antennas (Mio et al. 2007). TRPC channels are involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia (Fan et al. 2018). The structure in a lipid-occupied, closed state has been solved at 3.3 Å resolution. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. Fan et al. 2018 identified two lipid binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located. The cytoplasmic domain allosterically modulates channel gating (Sierra-Valdez et al. 2018). This channel may be present in mitochondria (Parrasia et al. 2019). TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans. Guo et al. 2022 reported the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. They identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are structurally and functionally conserved in TRPC6. The GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets revealed different conformations of the transmembrane domain (Guo et al. 2022). TRPC3 is primarily gated by lipids, and its surface expression is dependent on cholesterol (Clarke et al. 2022).

Accession Number:Q13507
Protein Name:Short transient receptor potential channel 3 (TrpC3) (Htrp-3) (Htrp3)
Length:848
Molecular Weight:97355.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:9
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate cation, inorganic cation, calcium(2+)

Cross database links:

RefSeq: NP_001124170.1    NP_003296.1   
Entrez Gene ID: 7222   
Pfam: PF00520    PF08344   
OMIM: 602345  gene
KEGG: hsa:7222   

Gene Ontology

GO:0005887 C:integral to plasma membrane
GO:0005515 F:protein binding
GO:0015279 F:store-operated calcium channel activity
GO:0006816 P:calcium ion transport
GO:0007602 P:phototransduction
GO:0055085 P:transmembrane transport

References (11)

[1] “trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry.”  Zhu X.et.al.   8646775
[2] “Coassembly of TRP and TRPL produces a distinct store-operated conductance.”  Xu X.-Z.S.et.al.   9215637
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[4] “TRPC1, a human homolog of a Drosophila store-operated channel.”  Wes P.D.et.al.   7568191
[5] “The membrane topology of human transient receptor potential 3 as inferred from glycosylation-scanning mutagenesis and epitope immunocytochemistry.”  Vannier B.et.al.   9535843
[6] “Receptor-activated Ca2+ influx via human Trp3 stably expressed in human embryonic kidney (HEK)293 cells. Evidence for a non-capacitative Ca2+ entry.”  Zhu X.et.al.   9417057
[7] “Functional interaction between InsP3 receptors and store-operated Htrp3 channels.”  Kiselyov K.et.al.   9853757
[8] “Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.”  Hofmann T.et.al.   9930701
[9] “Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry.”  Boulay G.et.al.   10611319
[10] “MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC.”  Lussier M.P.et.al.   15757897
[11] “RNF24, a new TRPC interacting protein, causes the intracellular retention of TRPC.”  Lussier M.P.et.al.   17850865
Structure:
5ZBG   6CUD   6D7L   6DJS     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MEGSPSLRRM TVMREKGRRQ AVRGPAFMFN DRGTSLTAEE ERFLDAAEYG NIPVVRKMLE 
61:	ESKTLNVNCV DYMGQNALQL AVGNEHLEVT ELLLKKENLA RIGDALLLAI SKGYVRIVEA 
121:	ILNHPGFAAS KRLTLSPCEQ ELQDDDFYAY DEDGTRFSPD ITPIILAAHC QKYEVVHMLL 
181:	MKGARIERPH DYFCKCGDCM EKQRHDSFSH SRSRINAYKG LASPAYLSLS SEDPVLTALE 
241:	LSNELAKLAN IEKEFKNDYR KLSMQCKDFV VGVLDLCRDS EEVEAILNGD LESAEPLEVH 
301:	RHKASLSRVK LAIKYEVKKF VAHPNCQQQL LTIWYENLSG LREQTIAIKC LVVLVVALGL 
361:	PFLAIGYWIA PCSRLGKILR SPFMKFVAHA ASFIIFLGLL VFNASDRFEG ITTLPNITVT 
421:	DYPKQIFRVK TTQFTWTEML IMVWVLGMMW SECKELWLEG PREYILQLWN VLDFGMLSIF 
481:	IAAFTARFLA FLQATKAQQY VDSYVQESDL SEVTLPPEIQ YFTYARDKWL PSDPQIISEG 
541:	LYAIAVVLSF SRIAYILPAN ESFGPLQISL GRTVKDIFKF MVLFIMVFFA FMIGMFILYS 
601:	YYLGAKVNAA FTTVEESFKT LFWSIFGLSE VTSVVLKYDH KFIENIGYVL YGIYNVTMVV 
661:	VLLNMLIAMI NSSYQEIEDD SDVEWKFARS KLWLSYFDDG KTLPPPFSLV PSPKSFVYFI 
721:	MRIVNFPKCR RRRLQKDIEM GMGNSKSRLN LFTQSNSRVF ESHSFNSILN QPTRYQQIMK 
781:	RLIKRYVLKA QVDKENDEVN EGELKEIKQD ISSLRYELLE DKSQATEELA ILIHKLSEKL 
841:	NPSMLRCE