Voltage-gated calcium channels (VGCCs), especially Ca v 2.1 and Ca v 2.2, are the major mediators of Ca 2+ influx at the presynaptic membrane in response to neuron excitation, thereby exerting a predominant control on synaptic transmission. To guarantee the timely and precise release of neurotransmitters at synapses, the activity of presynaptic VGCCs is tightly regulated by a variety of factors, including auxiliary subunits, membrane potential, G protein-coupled receptors (GPCRs), calmodulin (CaM), Ca 2+ -binding proteins (CaBP), protein kinases, various interacting proteins, alternative splicing events, and genetic variations.