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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/G187    most recent 00047.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shi, X.-Z. Articles by Sarna, S. K. PubMed PubMed Citation Articles by Shi, X.-Z. Articles by Sarna, S. K.

NEUROREGULATION AND MOTILITY

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

¹Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, and ²Department of Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas

Submitted 30 January 2008 ; accepted in final form 5 May 2008

Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the _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 _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 _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 _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 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, whereas VPAC receptor antagonists may serve as potential antimotility agents in diarrhea-like conditions produced by enhanced motility function.

diarrhea; constipation; 5-HT; 5-HT₄ receptor agonists; prokinetic agents; irritable bowel syndrome