title: TRPC channels as STIM1-regulated store-operated channels.
abstract: Receptor-activated Ca(2+) influx is mediated largely by store-operated channels (SOCs). TRPC channels mediate a significant portion of the receptor-activated Ca(2+) influx. However, whether any of the TRPC channels function as a SOC remains controversial. Our understanding of the regulation of TRPC channels and their function as SOCs is being reshaped with the discovery of the role of STIM1 in the regulation of Ca(2+) influx channels. The findings that STIM1 is an ER resident Ca(2+) binding protein that regulates SOCs allow an expanded and molecular definition of SOCs. SOCs can be considered as channels that are regulated by STIM1 and require the clustering of STIM1 in response to depletion of the ER Ca(2+) stores and its translocation towards the plasma membrane. TRPC1 and other TRPC channels fulfill these criteria. STIM1 binds to TRPC1, TRPC2, TRPC4 and TRPC5 but not to TRPC3, TRPC6 and TRPC7, and STIM1 regulates TRPC1 channel activity. Structure-function analysis reveals that the C-terminus of STIM1 contains the binding and gating function of STIM1. The ERM domain of STIM1 binds to TRPC channels and a lysine-rich region participates in the gating of SOCs and TRPC1. Knock-down of STIM1 by siRNA and prevention of its translocation to the plasma membrane inhibit the activity of native SOCs and TRPC1. These findings support the conclusion that TRPC1 is a SOC. Similar studies with other TRPC channels demonstrate their regulation by STIM1 and indicate that all TRPC channels, except TRPC7, function as SOCs.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. pworley@jhmi.edu
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zeng
authors.forename: Guo N
authors.initials: GN
authors.lastname: Huang
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Yuan
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D029721:Drosophila Proteins / Q000737:chemistry / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology; D017434:Protein Structure, Tertiary; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; C502662:Stim protein, Drosophila; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels