Voltage-gated calcium ion channels (CaV) link neuronal activity to a direct and rapid change in intracellular calcium. The resulting calcium signal, at the inner face of the plasma membrane, triggers a myriad of cellular responses depending on its location, magnitude, and duration. Presynaptic calcium entry through CaV2 (P, N, R -types) channels and, at some synapses CaV1 (L-type) channels triggers transmitter release, whereas calcium that enters through dendritic postsynaptic CaV1 channels regulates gene expression. Their strategic location at both sides of the synapse places voltage-gated calcium ion channels in a privileged position to integrate electrical and chemical signals, and to influence synaptic efficacy. Presynaptic CaV2.2 (N-type) channels are major targets of a large number of neurotransmitters and drugs, including morphine, that act through their respective G protein coupled receptors (GPCR) to modulate neuronal activity. This signaling pathway – GPCR to CaV2.2 channel – underlies presynaptic inhibition of transmitter release at many synapses. The actions of GPCRs on CaV2.2 channels are cell-type and synapse specific. Our studies show that cell-type specific alternative pre-mRNA splicing sets the sensitivity of CaV2.2 channels to GPCR inhibition. Cell-specific splicing factors therefore influence the efficacy of G protein signaling to CaV2.2 channels and ultimately synaptic function.