N-type voltage-gated calcium (Ca_V2.2) channels are expressed in neurons and targeted to the plasma membrane of presynaptic terminals, facilitating neurotransmitter release. Here, we find that the adaptor protein complex-1 (AP-1) mediates trafficking of Ca_V2.2 from the trans-Golgi network to the cell surface. Examination of splice variants of Ca_V2.2, containing either exon 37a (selectively expressed in nociceptors) or 37b in the proximal C terminus, reveal that canonical AP-1 binding motifs, YxxΦ and [DE]xxxL[LI], present only in exon 37a, enhance intracellular trafficking of exon 37a-containing Ca_V2.2 to the axons and plasma membrane of rat DRG neurons. Finally, we identify differential effects of dopamine-2 receptor (D2R) and its agonist-induced activation on trafficking of Ca_V2.2 isoforms. D2R slowed the endocytosis of Ca_V2.2 containing exon 37b, but not exon 37a, and activation by the agonist quinpirole reversed the effect of the D2R. Our work thus reveals key mechanisms involved in the trafficking of N-type calcium channels.SIGNIFICANCE STATEMENTCa_V2.2 channels are important for neurotransmitter release, but how they are trafficked is still poorly understood. Here, we describe a novel mechanism for trafficking of Ca_V2.2 from the trans-Golgi network to the cell surface which is mediated by the adaptor protein AP-1. Alternative splicing of exon 37 produces Ca_V2.2-exon 37a, selectively expressed in nociceptors, or Ca_V2.2-exon 37b, which is the major splice isoform. Our study reveals that canonical AP-1 binding motifs (YxxΦ and [DE]xxxL[LI]), present in exon 37a, but not 37b, enhance intracellular trafficking of exon 37a-containing Ca_V2.2 to axons and plasma membrane of DRG neurons. Interaction of APs with Ca_V2.2 channels may also be key underlying mechanisms for differential effects of the dopamine D₂receptor on trafficking of Ca_V2.2 splice variants.