Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are the inhibitory neurotransmitters in the gut wall. The mechanisms of the non-genomic effects of these neurotransmitters in smooth muscle relaxation have been investigated extensively over the last several decades. The genomic effects of these neurotransmitters on smooth muscle function are not known. VIP and PACAP, on binding to their receptors on smooth muscle cells, activate adenylate cyclase to produce cyclic 3'-5'adenosine monophosphate (cAMP) that mediates smooth muscle relaxation. However, cAMP is also a well known mediator of gene expression through the binding of transcription factor CRE binding protein (CREB) to the cAMP response element (CRE) on the promoters of its target genes. We have obtained substantial preliminary data that suggest an important novel function of the classic neurotransmitters VIP and PACAP to induce gene expression of the pore-forming alpha1C subunit of L-type Ca2+ channels in human colonic circular smooth muscle cells (HCCSMC). Ca2+ influx through these channels is an immediate early step in the signaling cascade for excitation-contraction coupling. Our preliminary data indicate that VIP/PACAP may also be anti-inflammatory neuropeptides that counter the initiation of the signaling cascade that activates the transcription factor NF-KB resulting in the suppression of cell contractility during inflammation. Based on these preliminary data our specific aims are to investigate: 1) VIP/PACAP-induced enhancement of alpha1C gene expression through cAMP/PKA signaling pathway in HCCSMC. 2) The cis- and trans-regulation of human ?1C promoter by VIP/PACAP-induced phosphorylation of the transcription factor CREB. 3) The interactions between cAMP/PKA, MAPK, PKC and CaMKII signaling pathways for the induction of alpha1C gene by VIP and PACAP. 4) The molecular and epigenetic mechanisms of the rnyo-protective role of VIP/PACAP in HCCSMC. This grant proposal presents a novel direction of research in the genomic regulation of smooth muscle function by two prominent and abundant neurotransmitters (VIP and PACAP) of the enteric inhibitory motor neurons. The findings will provide genomic and molecular insights into regulation of the expression of L-type calcium channels that play a critical role in excitation-contraction coupling in the normal state and during inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072414-05
Application #
7672318
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
2005-09-15
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$301,671
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Choi, Kuicheon; Chen, Jinghong; Mitra, Sankar et al. (2011) Impaired integrity of DNA after recovery from inflammation causes persistent dysfunction of colonic smooth muscle. Gastroenterology 141:1293-301, 1301.e1-3
Winston, John H; Xu, Guang-Yin; Sarna, Sushil K (2010) Adrenergic stimulation mediates visceral hypersensitivity to colorectal distension following heterotypic chronic stress. Gastroenterology 138:294-304.e3
Li, Qingjie; Sarna, Sushil K (2009) Nuclear myosin II regulates the assembly of preinitiation complex for ICAM-1 gene transcription. Gastroenterology 137:1051-60, 1060.e1-3
Choudhury, Barun K; Shi, Xuan-Zheng; Sarna, Sushil K (2009) Gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in a model of postinfective IBS. Am J Physiol Gastrointest Liver Physiol 296:G632-42
Shi, Xuan-Zheng; Sarna, Sushil K (2009) Homeostatic and therapeutic roles of VIP in smooth muscle function: myo-neuroimmune interactions. Am J Physiol Gastrointest Liver Physiol 297:G716-25
Choudhury, Barun K; Shi, Xuan-Zheng; Sarna, Sushil K (2009) Norepinephrine mediates the transcriptional effects of heterotypic chronic stress on colonic motor function. Am J Physiol Gastrointest Liver Physiol 296:G1238-47
Shi, Xuan-Zheng; Sarna, Sushil K (2008) Gene therapy of Cav1.2 channel with VIP and VIP receptor agonists and antagonists: a novel approach to designing promotility and antimotility agents. Am J Physiol Gastrointest Liver Physiol 295:G187-G196
Sarna, Sushil K (2008) Are interstitial cells of Cajal plurifunction cells in the gut? Am J Physiol Gastrointest Liver Physiol 294:G372-90
Shi, Xuan-Zheng; Choudhury, Barun K; Pasricha, Pankaj J et al. (2007) A novel role of VIP in colonic motility function: induction of excitation-transcription coupling in smooth muscle cells. Gastroenterology 132:1388-400
Sarna, Sushil K (2007) Enteric descending and afferent neural signaling stimulated by giant migrating contractions: essential contributing factors to visceral pain. Am J Physiol Gastrointest Liver Physiol 292:G572-81

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