Calcium: a fundamental regulator of intracellular membrane fusion?

Abstract

For many years, it has been known that an increase in cytosolic calcium triggers the fusion of secretory granules and synaptic vesicles with the plasma membrane. However, the role of calcium in the intracellular membrane-fusion reactions that coordinate the secretory and endocytic pathways has been less clear. Initially, there was accumulating evidence to indicate that a focally localized and transient calcium signal is required to trigger even those fusion events formerly classified as 'constitutive'-that is, those that normally occur in the absence of global cytosolic calcium increases. Therefore, calcium seemed to be a required fundamental co-factor underlying all biological membrane-fusion steps, perhaps with a conserved mechanism of action. However, although such unification would be gratifying, new data indicate that several intracellular fusion events do not require calcium after all. In this review, the evidence for calcium requirements and its modes of action in constitutive trafficking are discussed. As a challenging perspective, I suggest that the specific absence of calcium requirements for some transport steps in fact expands the function of calcium in trafficking, because divergent luminal calcium concentrations and requirements for fusion might increase the specificity with which intracellular membrane-fusion partners are determined.

Figure 1

Models of calcium signalling in membrane fusion. Blue represents luminal and extracelluar calcium, with lighter shades representing lower concentrations. Blue-green represents cytosolic calcium. (A) Calcium-dependent with extrinsic trigger. Global or focally restricted cytosolic calcium elevation owing to cell signalling events triggers membrane fusion, for example in exocytosis. (B) Calcium-dependent with intrinsic trigger. Completion of docking and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) pairing triggers a transient, localized release of calcium from the lumens of the paired membranes, activating the fusion machinery. This model has been proposed for numerous ‘constitutive' fusion events. (C) Calcium-dependent regulation by steady-state calcium gradients. Constantly leaking luminal calcium regulates transport machinery. Different luminal calcium concentrations and/or leak rates of different organelles could differentially modulate processes, for example, coat-protein complex I (COPI)/COPII vesicle coating/uncoating. (D) Calcium-independent. Calcium is apparently not required at some steps, for example, yeast vacuole fusion and COPII vesicle/Golgi fusion. In some cases (not pictured), a calcium requirement could exist but be met by resting cytosolic calcium concentrations; in this scenario, basal cytosolic calcium would be a permissive co-factor but not a trigger or regulator.

Jesse C. Hay