Referenced in: none

Automatically associated channels: TRP , TRPC , TRPC1 , TRPC3 , TRPC4

Title: Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion.

Authors: Kwong Tai Cheng, Hwei Ling Ong, Xibao Liu, Indu S Ambudkar

Journal, date & volume: Adv. Exp. Med. Biol., 2011 , 704, 435-49

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21290310

Abstract
Store-operated Ca(2+) entry (SOCE) is activated in response to depletion of the ER-Ca(2+) stores by the ER Ca(2+) sensor protein, STIM1 which oligomerizes and moves to ER/PM junctional domains where it interacts with and activates channels involved in SOCE. Two types of channel activities have been described. I(CRAC), via Ca(2+) release-activated Ca(2+) (CRAC) channel, which displays high Ca(2+) selectivity and accounts for the SOCE and cell function in T lymphocytes, mast cells, platelets, and some types of smooth muscle and endothelial cells. Orai1 has been established as the pore-forming component of CRAC channels and interaction of Orai1 with STIM1 is sufficient for generation of the CRAC channel. Store depletion also leads to activation of relatively non-selective cation currents (referred to as I(SOC)) that contribute to SOCE in several other cell types. TRPC channels, including TRPC1, TRPC3, and TRPC4, have been proposed as possible candidate channels for this Ca(2+) influx. TRPC1 is the best characterized channel in this regard and reported to contribute to endogenous SOCE in many cells types. TRPC1-mediated Ca(2+) entry and cation current in cells stimulated with agonist or thapsigargin are inhibited by low [Gd(3+)] and 10-20 μM 2APB (conditions that block SOCE). Importantly, STIM1 also associates with and gates TRPC1 via electrostatic interaction between STIM1 ((684)KK(685)) and TRPC1 ((639)DD(640)). Further, store depletion induces dynamic recruitment of a TRPC1/STIM1/Orai1 complex and knockdown of Orai1 completely abrogates TRPC1 function. Despite these findings, there has been much debate regarding the activation of TRPC1 by store depletion as well as the role of Orai1 and STIM1 in SOC channel function. This chapter summarizes recent studies and concepts regarding the contributions of Orai1 and TRPC1 to SOCE. Major unresolved questions regarding functional interaction between Orai1 and TRPC1 as well as possible mechanisms involved in the regulation of TRPC channels by store depletion will be discussed.