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1.A.4.1.7
Short transient receptor channel 5 (TrpC5 or Htrp5) (transports Ca2+ and Sr2+ in the presence of Orai1 and STIM1 (TC# 1.A.52.1.1) (Ma et al., 2008). It is a cold-transducer in the peripheral nervous system (Zimmermann et al., 2011). A small-molecule inhibitor suppresses progressive kidney disease in rats (Zhou et al. 2017).  ORAI and TRP, and the transmembrane Ca2+ sensors, stromal interaction molecules (STIMs), are involved in thrombosis and thrombo-inflammation in platelets and immune cells. Disregulated store-operated Ca2+ (SOCE) fluxes in platelets and immune cells are responsible, and the potential of SOCE inhibition as a therapeutic option to prevent or treat arterial thrombosis as well as thrombo-inflammatory disease states such as ischemic stroke have been considered (Mammadova-Bach et al. 2019). The molecular architecture of the Galpha(i)-bound TRPC5 ion channel has been solved (Won et al. 2023). G-protein coupled receptors (GPCRs) and ion channels serve as key molecular switches through which extracellular stimuli are transformed into intracellular effects, and it has long been postulated that ion channels are direct effector molecules of the alpha subunit of G-proteins (Galpha; see TC family 8.A.43). Won et al. 2023 presented cryo-EM structures of the human TRPC5-Galpha(i3) complexes with a 4:4 stoichiometry in lipid nanodiscs. Galpha(i3) binds to the ankyrin repeat edge of TRPC5 ~ 50 Å away from the cell membrane. Electrophysiological analyses showed that Galpha(i3) increases the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP(2)), thereby rendering TRPC5 more easily opened in the cell membrane, where the concentration of PIP(2) is physiologically regulated. These observations show that ion channels are one of the direct effector molecules of Galpha proteins triggered by GPCR activation-providing a structural framework for unraveling the crosstalk between two major classes of transmembrane proteins: GPCRs and ion channels (Won et al. 2023).

Accession Number:Q9UL62
Protein Name:TrpC5
Length:973
Molecular Weight:111412.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:9
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate strontium(2+), calcium(2+)

Cross database links:

RefSeq: NP_036603.1   
Entrez Gene ID: 7224   
Pfam: PF00520    PF08344   
OMIM: 300334  gene
KEGG: hsa:7224   

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:0007399 P:nervous system development
GO:0055085 P:transmembrane transport

References (9)

[1] “Molecular cloning and characterization of TRPC5 (HTRP5), the human homologue of a mouse brain receptor-activated capacitative Ca(2+) entry channel.”  Sossey-Alaoui K.et.al.   10493832
[2] “The DNA sequence of the human X chromosome.”  Ross M.T.et.al.   15772651
[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] “A novel capacitative calcium entry channel expressed in excitable cells.”  Philipp S.et.al.   9687496
[5] “Subunit composition of mammalian transient receptor potential channels in living cells.”  Hofmann T.et.al.   12032305
[6] “MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC.”  Lussier M.P.et.al.   15757897
[7] “Inhibition of TRPC5 channels by Ca2+-binding protein 1 in Xenopus oocytes.”  Kinoshita-Kawada M.et.al.   15895247
[8] “RNF24, a new TRPC interacting protein, causes the intracellular retention of TRPC.”  Lussier M.P.et.al.   17850865
[9] “The phospholipid-binding protein SESTD1 is a novel regulator of the transient receptor potential channels TRPC4 and TRPC5.”  Miehe S.et.al.   20164195

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FASTA formatted sequence
1:	MAQLYYKKVN YSPYRDRIPL QIVRAETELS AEEKAFLNAV EKGDYATVKQ ALQEAEIYYN 
61:	VNINCMDPLG RSALLIAIEN ENLEIMELLL NHSVYVGDAL LYAIRKEVVG AVELLLSYRR 
121:	PSGEKQVPTL MMDTQFSEFT PDITPIMLAA HTNNYEIIKL LVQKRVTIPR PHQIRCNCVE 
181:	CVSSSEVDSL RHSRSRLNIY KALASPSLIA LSSEDPILTA FRLGWELKEL SKVENEFKAE 
241:	YEELSQQCKL FAKDLLDQAR SSRELEIILN HRDDHSEELD PQKYHDLAKL KVAIKYHQKE 
301:	FVAQPNCQQL LATLWYDGFP GWRRKHWVVK LLTCMTIGFL FPMLSIAYLI SPRSNLGLFI 
361:	KKPFIKFICH TASYLTFLFM LLLASQHIVR TDLHVQGPPP TVVEWMILPW VLGFIWGEIK 
421:	EMWDGGFTEY IHDWWNLMDF AMNSLYLATI SLKIVAYVKY NGSRPREEWE MWHPTLIAEA 
481:	LFAISNILSS LRLISLFTAN SHLGPLQISL GRMLLDILKF LFIYCLVLLA FANGLNQLYF 
541:	YYETRAIDEP NNCKGIRCEK QNNAFSTLFE TLQSLFWSVF GLLNLYVTNV KARHEFTEFV 
601:	GATMFGTYNV ISLVVLLNML IAMMNNSYQL IADHADIEWK FARTKLWMSY FDEGGTLPPP 
661:	FNIIPSPKSF LYLGNWFNNT FCPKRDPDGR RRRRNLRSFT ERNADSLIQN QHYQEVIRNL 
721:	VKRYVAAMIR NSKTHEGLTE ENFKELKQDI SSFRYEVLDL LGNRKHPRSF STSSTELSQR 
781:	DDNNDGSGGA RAKSKSVSFN LGCKKKTCHG PPLIRTMPRS SGAQGKSKAE SSSKRSFMGP 
841:	SLKKLGLLFS KFNGHMSEPS SEPMYTISDG IVQQHCMWQD IRYSQMEKGK AEACSQSEIN 
901:	LSEVELGEVQ GAAQSSECPL ACSSSLHCAS SICSSNSKLL DSSEDVFETW GEACDLLMHK 
961:	WGDGQEEQVT TRL