STIM-TRP pathways function and regulation of TRPC1: Contribution to Ca2+ entry activated by store depletion

Abstract

Store-operated Ca2+ entry (SOCE) is activated in response to depletion of the ER-Ca2+ stores. Upon Ca2+ store depletion, the ER Ca2+ sensor protein, STIM1, oligomerizes and moves to ER/PM junctional domains where it interacts with and activates channels involved in SOCE; namely Orai and TRPC channels. Orai1 is the primary pore-forming component of the highly Ca2+ selective CRAC channel. It is recruited to ER/PM junctional domains by STIM1 where it is gated via interaction with a specific C-terminal domain of STIM1. Thus Orai1 and STIM1 are sufficient for generation of functional CRAC channels. Store depletion also leads to activation of relatively non-selective cation channels, referred to SOC channels that contribute to SOCE in several other cell types. TRPC1 contributes to endogenous SOCE and SOC channel function in many cells types. In these cells, TRPC1-mediated Ca2+ entry and cation currents are stimulated with either agonist or thapsigargin, and inhibited by low [Gd3+] and 10-20 μM 2APB (conditions that block SOCE). STIM1 also associates with and gates TRPC1 via electrostatic interaction between STIM1 (684KK685) and TRPC1 (639DD640). Further, functional Orai1 is required for activation of TRPC1-SOCE and this has been associated with recruitment of a TRPC1/STIM1/Orai1 complex. However, there is ongoing debate regarding the activation of TRPC1 by store depletion as well as the role of Orai1 and STIM1 in regulating its function. This chapter will summarize recent studies and concepts regarding the contributions of Orai1 and TRPC1 to SOCE. We will discuss major unresolved questions regarding functional interaction between Orai1 and TRPC1 as well as possible mechanisms involved in the regulation of TRPC channels.