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 I_CRAC, 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 I_CRAC. 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. 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.

Keywords: Caveolin; ER-PM junctions; Lipid rafts; Orai1; SOCE; STIM1; TRPC.

Figure 1. Proposed model for TRPC1 activation

Following store depletion, STIM1 aggregates and translocates to the ER-PM junction. Orai1 is recruited to the STIM1 puncta resulting in CRAC channel activation. The resulting [Ca²⁺]_i increase leads to NFAT activation and insertion of TRPC1-containing vesicles into the plasma membrane (Modified from [55]). Insets in the figure show I-V relationships of the currents recorded under the various conditions; I_CRAC generated by Orai1+STIM1 (left) and I_SOC generated by combination of TRPC1+STIM1 and Orai1+STIM1 channels.

Figure 2. Regulation of TRPC1 trafficking and function

A. Model depicting the role of a rapid recycling pathway in the TRPC1 trafficking and function. TRPC1 is endocytosed from the plasma membrane by Arf6, sorted to Rab5 – early endosomes (EEs) and then is recycled back to the plasma membrane by Rab4-dependent fast recycling endosomes. This recycling carries TRPC1 to the cellular region near the plasma membrane where STIM1 clusters in response to ER – Ca²⁺ depletion. Within these ER–PM junctions, STIM1 interacts with and activates Orai1. Ca²⁺ entry via Orai1 triggers recruitment of TRPC1 from Rab4-vesicles into the plasma membrane, where the channel interacts with STIM1 and is activated. Thus, endocytic recycling via Rab4 determines clustering of TRPC1with STIM1, as well as plasma membrane insertion and function of the channel (Modified from [75]). B–C. Role of Rab4 and Rab5 on function of endogenous TRPC1 in the salivary gland cell line, HSG. Store-operated currents measured in HSG cells expressing Rab5-WT or dominant negative and spontaneously active Rab5 mutants (B) and HSG cells with Rab5 alone or Rab5+Rab4 (C).