TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces

Abstract

Store-operated calcium entry (SOCE) is a ubiquitous Ca2+ entry pathway that is activated in response to depletion of ER-Ca2+ stores and critically controls the regulation of physiological functions in miscellaneous cell types. The transient receptor potential canonical 1 (TRPC1) is the first member of the TRPC channel subfamily to be identified as a molecular component of SOCE. While TRPC1 has been shown to contribute to SOCE and regulate various functions in many cells, none of the reported TRPC1-mediated currents resembled ICRAC, the highly Ca2+-selective store-dependent current first identified in lymphocytes and mast cells. Almost a decade after the cloning of TRPC1 two proteins were identified as the primary components of the CRAC channel. The first, STIM1, is an ER-Ca2+ sensor protein involved in activating SOCE. The second, Orai1 is the pore-forming component of the CRAC channel. Co-expression of STIM1 and Orai1 generated robust ICRAC. Importantly, STIM1 was shown to also activate TRPC1 via its C-terminal polybasic domain, which is distinct from its Orai1-activating domain, SOAR. In addition, TRPC1 function critically depends on Orai1-mediated Ca2+ entry which triggers recruitment of TRPC1 into the plasma membrane where it is then activated by STIM1. More importantly, TRPC1 and Orai1 form discrete STIM1-gated channels that generate distinct Ca2+ signals and regulate specific cellular functions. Surface expression of TRPC1 can be modulated by trafficking of the channel to and from the plasma membrane, resulting in changes to the phenotype of TRPC1-mediated current and [Ca2+]i signals. Thus, TRPC1 is activated downstream of Orai1 and modifies the initial [Ca2+]i signal generated by Orai1 following store depletion. This review will summarize the important findings that underlie the current concepts for activation and regulation of TRPC1, as well as its impact on cell function.

TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis

“…Thus, the contribution of TMEM16A to EGF-induced Ca 2+ signaling appears to be particular related to the engagement of TMEM16A with EGFR. SOCE is usually described by the aggregation of STIM1 into punctae following the depletion of intracellular Ca 2+ stores, and their association with ORAI proteins at the plasma membrane to form functional Ca 2+ channels that mediate Ca 2+ influx (29,30).…”

Bradykinin‐mediated Ca2+ signalling regulates cell growth and mobility in human cardiac c‐Kit+ progenitor cells

“…48 Although there exist arguments on whether TRPC1 is a component of SOCE channel, 49 our recent results from human cardiac c-Kit + progenitor cells 13 support the notion that TRPC1 works together with Orai1 to form discrete STIM1-gated SOCE channel, mediate distinct Ca 2+ signals and regulate specific cellular functions. [50][51][52] The present study shows that bradykinin-induced Ca 2+ In Ca 2+ signalling, very low cytoplasmic Ca 2+ concentration can increase in a specific manner to trigger downstream cellular events, and every cell type in the human body utilizes some form of Ca 2+ signalling to function or survive. 29 Ferreira-Martins and colleagues reported that spontaneous Ca 2+ oscillations promote human cardiac c-Kit + progenitor cell proliferation.…”

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

“…In particular, there has been debate about the role or opening mechanisms of TRPC1. Initially, TRPC1 was claimed to take the role of a SOCE in regulating Orai1-mediated Ca 2+ entry (Ambudkar et al, 2017). Consistent with this claim, the role of TRPC1 in AD has been reported by Linde et al (2011).…”