The TR (i)P to Ca²⁺ signaling just got STIMy: an update on STIM1 activated TRPC channels

Abstract

Calcium is a ubiquitous signaling molecule, indispensable for cellular metabolism of organisms from unicellular life forms to higher eukaryotes. The biological function of most eukaryotic cells is uniquely regulated by changes in cytosolic calcium, which is largely achieved by the universal phenomenon of store-operated calcium entry (SOCE). The canonical TRPs and Orai channels have been described as the molecular components of the store-operated calcium channels (SOCC). Importantly, the ER calcium-sensor STIM1 has been shown to initiate SOCE via gating of SOCC. Since the discovery of STIM1, as the critical regulator of SOCE, there has been a flurry of observations suggesting its obligatory role in regulating TRPC and Orai channel function. Considerable effort has been made to identify the molecular details as how STIM1 activates SOCC. In this context, findings as of yet has substantially enriched our understanding on, the modus operandi of SOCE, the distinct cellular locales that organize STIM1-SOCC complexes, and the physiological outcomes entailing STIM1-activated SOCE. In this review we discuss TRPC channels and provide an update on their functional regulation by STIM1.

Figure 1

STIM1 activated SOCE. The current molecular concept of SOCE is STIM1-mediated activation of PM-SOCC (TRPC/Orai channels). Agonist-induced receptor (GPCR/RTK) activation results in PLC-mediated hydrolysis of PIP2, generating the diffusible and membrane-bound cellular messengers – DAG (diacylglycerol) and IP₃ respectively. IP₃ binds to its receptor (IP₃Rs) in the ER depleting the ER Ca²⁺ stores. This leads to STIM1 oligomerization by interaction of mono- or dimeric STIM1 molecules. The STIM1 oligomeric-clusters thus formed are subsequently recruited to ER-PM juxtaposed sites allowing STIM1 to physically activate the TRPC and Orai channels to bring about Ca²⁺ entry. This raises the (Ca²⁺)_cyt which results in store-operated Ca²⁺ signaling and influences a variety of cellular functions. To complete the SOCE cycle, (Ca²⁺)_cyt is sequestered back to the ER by the SERCA pump and/or extruded to the cells’ exterior by PMCA. The membrane-associated lipid messenger - DAG also has the ability to activate select TRPC channels independent of ER-stores and presumably STIM1 as well.

Figure 2

STIM1 domains. This model (not drawn to scale) depicts the critical domains of STIM1 with its N-terminal in the ER lumen and the C-terminal in the cytosol. The amino acids that span individual domain are shown within parentheses. The lysine (K) residues, critical for TRPC channel gating (shown in orange), lie within the poly-K region in the cytoplasmic domain on STIM1. The cytoplasmic domain of STIM1 also contains the overlapping Orai1 activating regions (CAD/SOAR). Shown in blue are the residues that are glycosylated (N-terminal) or phosphorylated on serine (C-terminal). Abbreviations - c/hEF hand (canonical/hidden), SAM (sterile alpha motif), TM (trans membrane), CC1/2 (coiled-coil), ERM (Ezrin-Radixin-Moesin), CAD (CRAC activation domain), SOAR (STIM1 Orai activating region)

Figure 3

Steps in TRPC1 channel activation. This model shows the compartmentalization TRPC1-mediated Ca²⁺ influx at ER-caveolar/membrane raft juxtaposed microdomains. In ‘Resting’ state (ER-stores filled)- (a) STIM1, predominantly in the ER, is bound to Ca²⁺ and displays a diffused localization pattern, (b) PM-associated STIM1 is also shown, however, its contextual relevance is currently unknown, (c) PM-TRPC1 differentially associates with caveolin1 (cav1) enriched - caveolar and non-caveolar microdomains and (d) a steady-state PM trafficking of TRPC1 is achieved by vesicular activity. Between resting and activation, we propose an intermediate step of channel ‘Recruitment’, wherein, following ER Ca²⁺ store-depletion (step-I), (a) STIM1 unbinds Ca²⁺ and engages in oligomeric cluster (puncta) formation, (b) TRPC1 is recruited to caveolar raft domains wherein Cav1 scaffolds PM-TRPC1 thus retaining the channel at discrete ER apposed PM microdomains. The channel ‘Activation’ is marked by SOCE initiation (step II) where, (a) STIM1 interacts with TRPC1 and (b) activates the channel resulting in the increase of (Ca²⁺)_cyt with the subsequent dissociation of Cav1. (Ca²⁺)_cyt is then sequestered back to the ER to refill the ER-stores as indicated by store replete (step III), following which (a) STIM1 binds Ca²⁺ and dissociates from TRPC1 getting back to the resting state. As the filled status of ER controls the STIM1-puncta kinetics it also determines the dynamic and reversible STIM1-TRPC1 associations. The molecular events ensuing each step (step I through step III) outlined in this model may not necessarily reflect their exact physiological sequence and further investigation in this aspect is necessary to delineate the exact

Figure 4

STIM1 activated SOCE and cell function. This model illustrates downstream signaling following STIM1-activated SOCE. Activation of PM-SOCC (TRPC/Orai channels) by STIM1 accounts for store-operated Ca²⁺ signaling following increase in (Ca²⁺)_cyt. To impact on cell signaling, the SOCE-induced (Ca²⁺)_cyt reciprocates with organelle such as mitochondria and signaling intermediates including kinases (such as PKC, CaMKs, ERK), phosphatases (such as calcineurin) and Ca²⁺ binding proteins like calmodulin. On a long term, SOCE influences a variety of cellular functions and brings about observable physiological changes by gene regulation. As STIM1 has the potential to influence many signaling pathways, it might be pivotal to studying pathological mysteries such as cancer and neurodegeneration.