Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the _1C subunit of Ca_v1.2 (L-type) Ca²⁺ channels in primary cultures of the human colonic circular smooth muscle cells and circular smooth muscle strips. In this study, we investigated whether systemic infusion of VIP at low concentrations in intact animals enhances the gene transcription and protein expression of these channels to accelerate colonic transit. We also investigated whether similar systemic infusions of VPAC_1/2 receptor antagonist retards colonic transit by suppressing the gene expression of the _1C subunit. We found that the systemic infusion of VIP for seven days by a surgically implanted osmotic pump enhances the gene and protein expression of the _1C subunit, and circular muscle contractility in the proximal and the middle rat colons, but not the distal colon. A similar systemic infusion of VPAC_1/2 receptor antagonist suppresses the expression of the _1C subunit and circular smooth muscle contractility in the proximal and the middle colons. The VIP infusion also accelerates colonic transit and pellet defecation by rats, whereas, the infusion of VPAC_1/2 receptor antagonist retards colonic transit and pellet defecation. VPAC₁ receptors, but not VPAC₂ receptors, mediate the above gene-transcription induced promotility effects of VIP. We conclude that VIP and VPAC₁ receptor agonists may serve as potential promotility agents in constipation-like conditions, while VPAC receptor antagonists may serve as potential anti-motility agents in diarrhea-like conditions produced by enhanced motility function.