Gene therapy of Cav1.2 channel with VIP and VIP receptor agonists and antagonists

A novel approach to designing promotility and antimotility agents

Xuan-Zheng Shi, Sushil K. Sarna

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the α1C subunit of Cav1.2 (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 VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the α1C 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 α1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the α1C 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 VPAC1/2 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume295
Issue number1
DOIs
StatePublished - Jul 2008

Fingerprint

Receptors, Vasoactive Intestinal Polypeptide, Type I
Vasoactive Intestinal Peptide Receptors
Genetic Therapy
Colon
Defecation
Smooth Muscle
Gene Expression
Constipation
Genes
Smooth Muscle Myocytes
Neurotransmitter Agents
Diarrhea
Proteins
Muscles

Keywords

  • 5-HT
  • 5-HT receptor agonists
  • Constipation
  • Diarrhea
  • Irritable bowel syndrome
  • Prokinetic agents

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

@article{6a93942d5ae94a498a71f523382dee56,
title = "Gene therapy of Cav1.2 channel with VIP and VIP receptor agonists and antagonists: A novel approach to designing promotility and antimotility agents",
abstract = "Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the α1C subunit of Cav1.2 (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 VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the α1C 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 α1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the α1C 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 VPAC1/2 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.",
keywords = "5-HT, 5-HT receptor agonists, Constipation, Diarrhea, Irritable bowel syndrome, Prokinetic agents",
author = "Xuan-Zheng Shi and Sarna, {Sushil K.}",
year = "2008",
month = "7",
doi = "10.1152/ajpgi.00047.2008",
language = "English (US)",
volume = "295",
journal = "American Journal of Physiology - Endocrinology and Metabolism",
issn = "0193-1849",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - Gene therapy of Cav1.2 channel with VIP and VIP receptor agonists and antagonists

T2 - A novel approach to designing promotility and antimotility agents

AU - Shi, Xuan-Zheng

AU - Sarna, Sushil K.

PY - 2008/7

Y1 - 2008/7

N2 - Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the α1C subunit of Cav1.2 (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 VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the α1C 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 α1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the α1C 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 VPAC1/2 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.

AB - Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the α1C subunit of Cav1.2 (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 VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the α1C 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 α1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the α1C 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 VPAC1/2 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.

KW - 5-HT

KW - 5-HT receptor agonists

KW - Constipation

KW - Diarrhea

KW - Irritable bowel syndrome

KW - Prokinetic agents

UR - http://www.scopus.com/inward/record.url?scp=51149102095&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=51149102095&partnerID=8YFLogxK

U2 - 10.1152/ajpgi.00047.2008

DO - 10.1152/ajpgi.00047.2008

M3 - Article

VL - 295

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 1

ER -