STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels.
Stromal interacting molecule 1 (STIM1) is a Ca(2+) sensor that conveys the Ca(2+) load of the endoplasmic reticulum to store-operated channels (SOCs) at the plasma membrane. Here, we report that STIM1 binds TRPC1, TRPC4 and TRPC5 and determines their function as SOCs. Inhibition of STIM1 function inhibits activation of TRPC5 by receptor stimulation, but not by La(3+), suggesting that STIM1 is obligatory for activation of TRPC channels by agonists, but STIM1 is not essential for channel function. Through a distinct mechanism, STIM1 also regulates TRPC3 and TRPC6. STIM1 does not bind TRPC3 and TRPC6, and regulates their function indirectly by mediating the heteromultimerization of TRPC3 with TRPC1 and TRPC6 with TRPC4. TRPC7 is not regulated by STIM1. We propose a new definition of SOCs, as channels that are regulated by STIM1 and require the store depletion-mediated clustering of STIM1. By this definition, all TRPC channels, except TRPC7, function as SOCs.
Yuan
Joseph P
JP
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Zeng
Weizhong
W
Huang
Guo N
GN
Worley
Paul F
PF
Muallem
Shmuel
S
D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D018679:Cholinergic Agonists / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D018679:Cholinergic Agonists; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D021122:Protein Subunits; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D005682:Gadolinium; D002118:Calcium