Gene therapy of Ca_v1.2 channel with VIP and VIP receptor agonists and antagonists: A novel approach to designing promotility and antimotility agents

Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the α_1C subunit of Ca_v1.2 (L-type) Ca²⁺ channels in the primary cultures of human colonic circular smooth muscle cells and circular smooth muscle strips. In this study, we investigated whether systemic infusion of VIP 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 repressing the constitutive gene expression of the α_1C subunit. We found that the systemic infusion of VIP for 7 days by a surgically implanted osmotic pump enhances the gene and protein expression of the α_1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC_1/2 receptor antagonist represses the expression of the α_1C subunit and circular smooth muscle contractility in the proximal and the middle colons. The VIP infusion 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 VPAC ₂ 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, whereas VPAC receptor antagonists may serve as potential antimotility agents in diarrhea-like conditions produced by enhanced motility function.