Calcium channel regulation and presynaptic plasticity

Voltage-gated calcium (Ca2+) channels initiate release of neurotransmitters at synapses, and regulation of presynaptic Ca2+ channels has a powerful influence on synaptic strength. Presynaptic Ca2+ channels form a large signaling complex, which targets synaptic vesicles to Ca2+ channels for efficient release and mediates Ca2+ channel regulation. Presynaptic plasticity regulates synaptic function on the timescale of milliseconds to minutes in response to neurotransmitters and the frequency of action potentials. This article reviews the regulation of presynaptic Ca2+ channels by effectors and regulators of Ca2+ signaling and describes the emerging evidence for a critical role of Ca2+ channel regulation in control of neurotransmission and in presynaptic plasticity. Failure of function and regulation of presynaptic Ca2+ channels leads to migraine, ataxia, and potentially other forms of neurological disease. We propose that presynaptic Ca2+ channels serve as the regulatory node in a dynamic, multilayered signaling network that exerts short-term control of neurotransmission in response to synaptic activity.