SOCIC: The store-operated calcium influx complex

Abstract

Depletion of intracellular calcium stores via activation of G-protein-coupled receptors associated to the inositol trisphosphate cascade, or by the blockade of the endoplasmic reticulum calcium APTase (SERCA) results in the activation of calcium influx via the so-called store-operated channels (SOCs).

The recent identification of STIM1 as the putative sensing molecule responsible for communicating the depleted state of intracellular calcium stores to the plasma membrane channel highlights the relevance of protein complexes in calcium signaling. Further developments in this area identify Orai as part of the store-operated channel complex. Upon depletion of intracellular calcium stores, STIM1 (at the ER) and Orai (at the plasma membrane) aggregate into macromolecular complexes. This molecular aggregation appears to be necessary to induce activation of calcium influx. Several studies have identified novel members from what I would like to define here as the store-operated calcium influx complex (SOCIC), such as the TRPC1 channel, SERCA and the microtubule end tracking protein, EB1. An orchestrated series of events involving the association and dissociation of several protein complexes culminate with the activation of calcium influx upon depletion of the ER. There are other likely players in this sophisticated signaling mechanism, waiting to be uncovered.

The SOCIC assembly does not appear to occur in random areas of the plasma membrane, but rather in highly specialized areas known as lipid raft domains. These results strongly suggest that not only proteins but lipids also may be part or active players in the modulation of the store-operated calcium entry (SOCE).

In this review we will analyze the evidence supporting macromolecular complex assembly as a prerequisite for SOC activation. We will highlight the evidence showing novel members from SOCIC and speculate about possible yet undiscovered members and players in this highly regulated calcium signaling mechanism. Finally we will discuss about the role of lipid raft domains in controlling store- and agonist-activated calcium influx.

Introduction

Calcium is a universal messenger involved in a wide variety of signaling processes, from cell division to apoptosis, from cell differentiation to cancer. The wealth of events in normal function and disease controlled by calcium is overwhelming [1].

A conundrum in modern biology is how a cell or tissue distinguishes the specific meaning of that signal, for instance, to initiate cell proliferation or apoptosis (two events that are in essence contradictory) in response to elevations in intracellular calcium [1]. One possible key used by cells to identify the nature of the signal is the amount in the calcium increment. One could envision thresholds of calcium capable of activating a given signaling pathway, leading to a particular response. The problem with this hypothesis is that most calcium-dependent proteins are activated by concentrations of calcium within the same range [1]. Another possible key is the spatial localization in the calcium increment. In this regard, several studies have identified what is now known as calcium microdomains [2].

Recent evidence provides clues about a novel and rather interesting solution to this conundrum, which involves changes in protein function that may influence how these proteins recognize or interact with calcium [2], [3]. Such changes include associations of proteins into macromolecular complexes or interactions of the effector proteins with lipids [4], [5], [6], [7]. In this direction, lipid rafts represent a complex solution by controlling the localization of effectors on specialized domains in the plasma membrane (PM), and in particular cases, associating these domains to other cellular structures, such as the endoplasmic reticulum (ER).

The bidirectional communication between the plasma membrane and the ER to control calcium influx was evidenced many years ago [8]. Depletion of intracellular calcium stores leads to the activation of calcium influx via the so-called store-operated channels (SOC). Replenishing the calcium stores shuts down SOC and resets the system [9], [10], [11]. This mechanism is essential for the refilling of the ER and to perpetuate calcium signaling in the cell [9], [10], [11].

One key event in this process is the signal communicating the depleted state of intracellular calcium stores to the plasmalemmal channel [9], [10]. The recent identification of the stromal interacting molecule (STIM1) as the putative sensor responsible for communicating the depletion of the ER to the PM was a major advance in the field [10]. Further studies showing Orai as the protein forming part of the SOC was another important step towards understanding the molecular basis of the store-operated calcium entry (SOCE) (for review see [10]).

Upon depletion of the ER, STIM1 (at the ER) and Orai (at the PM) aggregate into macromolecular complexes [3], [12]. This molecular aggregation appears to be necessary to induce activation of calcium influx [12]. Several studies indicate that TRPC1, a member from the TRP superfamily of channels, is part of the SOC macromolecular complex (for review see [13]). Furthermore, recent studies position the SERCA [3], [14], [15] and the microtubule end binding protein (EB1) [3], [16] as novel members from what I would like to define here as the store-operated calcium influx complex (SOCIC).

Recently published data indicate that not only proteins are involved in the SOCIC, but lipids too. Experimental evidence suggests that SOC macromolecular complex formation occur in lipid raft domains at the plasma membrane [3], [17], [18], [19], [20], [21], [22]. Even more, there is solid evidence provided by different groups showing that disruption of lipid rafts affect SOCE [4], [17], [20], [23].

In this review we will analyze the evidence showing macromolecular complex assembly as a prerequisite for SOC activation. We will review the evidence showing novel members from SOCIC and speculate about possible yet undiscovered members. Finally we will discuss about the role of lipid raft domains in controlling SOCIC assembly and activation.