Calmodulin as a major calcium buffer shaping vesicular release and short-term synaptic plasticity: facilitation through buffer dislocation

摘要

Action potential-dependent release of synaptic vesicles and short-term synaptic plasticity are dynamically regulated by the endogenous Ca²⁺ buffers that shape [Ca²⁺] profiles within a presynaptic bouton. Calmodulin is one of the most abundant presynaptic proteins and it binds Ca²⁺ faster than any other characterized endogenous neuronal Ca²⁺ buffer. Direct effects of calmodulin on fast presynaptic Ca²⁺ dynamics and vesicular release however have not been studied in detail. Using experimentally constrained three-dimensional diffusion modeling of Ca²⁺ influx–exocytosis coupling at small excitatory synapses we show that, at physiologically relevant concentrations, Ca²⁺ buffering by calmodulin plays a dominant role in inhibiting vesicular release and in modulating short-term synaptic plasticity. We also propose a novel and potentially powerful mechanism for short-term facilitation based on Ca²⁺-dependent dynamic dislocation of calmodulin molecules from the plasma membrane within the active zone.