Regulation of Presynaptic CaV2.1 Channels by Ca2+ Sensor Proteins Mediates Short-Term Synaptic Plasticity

SummaryShort-term synaptic plasticity shapes the postsynaptic response to bursts of impulses and is crucial for encoding information in neurons, but the molecular mechanisms are unknown. Here we show that activity-dependent modulation of presynaptic CaV2.1 channels mediated by neuronal Ca2+ sensor proteins (CaS) induces synaptic plasticity in cultured superior cervical ganglion (SCG) neurons. A mutation of the IQ-like motif in the C terminus that blocks Ca2+/CaS-dependent facilitation of the P/Q-type Ca2+ current markedly reduces facilitation of synaptic transmission. Deletion of the nearby calmodulin-binding domain, which inhibits CaS-dependent inactivation, substantially reduces depression of synaptic transmission. These results demonstrate that residual Ca2+ in presynaptic terminals can act through CaS-dependent regulation of CaV2.1 channels to induce short-term synaptic facilitation and rapid synaptic depression. Activity-dependent regulation of presynaptic CaV2.1 channels by CaS proteins may therefore be a primary determinant of short-term synaptic plasticity and information-processing in the nervous system.