TRPC Channels in the SOCE Scenario

Abstract

Transient receptor potential (TRP) proteins form non-selective Ca²⁺ permeable channels that contribute to the modulation of a number of physiological functions in a variety of cell types. Since the identification of TRP proteins in Drosophila, it is well known that these channels are activated by stimuli that induce PIP₂ hydrolysis. The canonical TRP (TRPC) channels have long been suggested to be constituents of the store-operated Ca²⁺ (SOC) channels; however, none of the TRPC channels generate Ca²⁺ currents that resemble I_CRAC. STIM1 and Orai1 have been identified as the components of the Ca²⁺ release-activated Ca²⁺ (CRAC) channels and there is a body of evidence supporting that STIM1 is able to gate Orai1 and TRPC1 in order to mediate non-selective cation currents named I_SOC. STIM1 has been found to interact to and activate Orai1 and TRPC1 by different mechanisms and the involvement of TRPC1 in store-operated Ca²⁺ entry requires both STIM1 and Orai1. In addition to the participation of TRPC1 in the I_SOC currents, TRPC1 and other TRPC proteins might play a relevant role modulating Orai1 channel function. This review summarizes the functional role of TRPC channels in the STIM1-Orai1 scenario.

Keywords: Orai1; STIM1; TRPC1; calcium influx; store-operated Ca2+ entry (SOCE).

Figure 1

Milestones in the characterization of Ca²⁺ entry. In the early 1880s, Ringer revealed the functional role of Ca²⁺ entry in heart contraction. About a century later, store-operated Ca²⁺ entry (SOCE) was discovered and, by that time, transient receptor potential (TRP) channels were identified, first in Drosophila and then in mammals. In 2005 and 2006 STIM1 and Orai1, the key components of the Ca²⁺ release-activated Ca²⁺ (CRAC) channels, were identified, and canonical TRP (TRPC) channels were found to participate in a non-selective store-operated current together with STIM1 and Orai1. The model represents two alternatives for the involvement of TRPC in the store-operated channels.

Figure 2

Cartoon depicting the activation of TRPC1 channels upon Ca²⁺ store depletion. (a) In the resting state, TRPC1 shows both plasma membrane and cytosolic localization. (b) Upon Ca²⁺ store depletion, Ca²⁺ influx via Orai1 has been reported to induce the translocation of intracellularly-located TRPC1 to the plasma membrane where it might be activated by STIM1. The model shows two alternatives for functional (mediating Ca²⁺ entry for the translocation of TRPC1 to the plasma membrane; left panel) or direct participation of Orai1 in the activation of TRPC1 (forming a STIM1–Orai1–TRPC1 ternary complex; right panel).

Figure 3

Overview of the modulation of Orai1 by TRPC channels. Orai1 channel function might be positively or negatively regulated by TRPC channels in the vicinity. (a) Ca²⁺ and Na⁺ entry through TRPC channels might lead to membrane depolarization and thus attenuation of the electrical gradient that favors Ca²⁺ influx via Orai1. (b) Ca²⁺ entry via TRPC channels participates in global rises in [Ca²⁺]_c, thus leading to Ca²⁺-dependent inactivation of Orai1 channels. (c) Some TRPC channels are required for Orai1 recycling at the plasma membrane.