Molecular determinants of TRPC1 regulation within ER–PM junctions

Abstract

Store-operated calcium entry (SOCE) is activated within the endoplasmic reticulum (ER)–plasma membrane (PM) junctions in the plasma membrane and involves assembly of the channels, Orai1 and TRPC1, with the regulatory protein, STIM1, in response to depletion of Ca2+ in the ER. The dynamic assembly of the channel complexes as well as regulation of channel activity and cell function is dependent on critical components that are either already localized in and/or recruited to the junctions following cell stimulation. These include proteins and lipids in the plasma membrane, ER, and cytosol. Together, these coordinated interactions lead to assembly and activation of Orai1/STIM1 and TRPC1/STIM1 channels. Recent studies demonstrate that Ca2+ signals generated by Orai1 are detected locally within the ER–PM junctions by various signaling proteins that trigger and regulate other Ca2+-dependent functions. One such function is the plasma membrane recruitment of TRPC1 channels where it is activated by STIM1. Activation of TRPC1 within the ER–PM junctions leads to generation of distinct [Ca2+]i signals and regulation of cellular functions different from those regulated by Orai1. Thus, it has been suggested that Orai1 and TRPC1 channels are compartmentalized in distinct microdomains. Such compartmentalization involves organization of plasma membrane lipids as well as structural and scaffolding proteins, the nature of which is still poorly understood. Importantly, there appears to be dynamic reorganization of the microdomains within existing ER–PM junctions that allow segregated proteins to interact. Together, these highly specific and coordinated remodeling of protein complexes and membrane domains results in generation of spatially- and temporally-controlled Ca2+ signals that are critical for numerous downstream cellular functions.