Multiple Ca2+ sensors in secretion: Teammates, competitors or autocrats?

Regulated neurotransmitter secretion depends on Ca ²⁺ sensors, C2 domain proteins that associate with phospholipids and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complexes to trigger release upon Ca ²⁺ binding. Ca ²⁺ sensors are thought to prevent spontaneous fusion at rest (clamping) and to promote fusion upon Ca ²⁺ activation. At least eight, often coexpressed, Ca ²⁺ sensors have been identified in mammals. Accumulating evidence suggests that multiple Ca ²⁺ sensors interact, rather than work autonomously, to produce the complex secretory response observed in neurons and secretory cells. In this review, we present several working models to describe how different sensors might be arranged to mediate synchronous, asynchronous and spontaneous neurotransmitter release. We discuss the scenario that different Ca ²⁺ sensors typically act on one shared vesicle pool and compete for binding the multiple SNARE complexes that are likely to assemble at single vesicles, to exert both clamping and fusion-promoting functions.