Store-Operated Ca²⁺ Entry (SOCE) Pathways

Hwei Ling Ong, Indu S. Ambudkar

Store-operated calcium entry (SOCE) is a ubiquitous Ca(2+) entry pathway that is activated in response to depletion of ER-Ca(2+) stores and critically controls the regulation of physiological functions in a wide variety of cell types. The transient receptor potential canonical (TRPC) channels (TRPCs 1-7), which are activated by stimuli leading to PIP2 hydrolysis, were first identified as molecular components of SOCE channels. While TRPC1 was associated with SOCE and regulation of function in several cell types, none of the TRPC members displayed I CRAC, the store-operated current identified in lymphocytes and mast cells. Intensive search finally led to the identification of Orai1 and STIM1 as the primary components of the CRAC channel. Orai1 was established as the pore-forming channel protein and STIM1 as the ER-Ca(2+) sensor protein involved in activation of Orai1. STIM1 also activates TRPC1 via a distinct domain in its C-terminus. However, TRPC1 function depends on Orai1-mediated Ca(2+) entry, which triggers recruitment of TRPC1 into the plasma membrane where it is activated by STIM1. TRPC1 and Orai1 form distinct store-operated Ca(2+) channels that regulate specific cellular functions. It is now clearly established that regulation of TRPC1 trafficking can change plasma membrane levels of the channel, the phenotype of the store-operated Ca(2+) current, as well as pattern of SOCE-mediated [Ca(2+)]i signals. Thus, TRPC1 is activated downstream of Orai1 and modifies the initial [Ca(2+)]i signal generated by Orai1. This review will highlight current concepts of the activation and regulation of TRPC1 channels and its impact on cell function.