Abstract

Substance P (SP) is a gut neuropeptide involved in physiological regulation and has also been implicated in gut inflammation. Physiological responses to SP have been shown to desensitize rapidly and extensively and SP receptors (SPR) appear to be up-regulated in inflammatory bowel disease. These observations suggest that the SPR is regulated but the characteristics and mechanisms of SPR regulation are largely unknown. This proposal describes studies designed to reveal mechanisms of SPR regulation.
The specific aims are to (1) determine the mechanisms of SPR desensitization, (2) determine the mechanisms of SPR resensitization, and (3) determine the mechanisms of SPR up- and down- regulation. These goals will be achieved by testing several critical hypotheses. Specifically, the role of phosphorylation of SPR as a mechanism of desensitization will be assessed by experimental strategies such as inhibition of specific protein kinases, analysis of desensitization of mutagenized SPRs in which specific putative phosphorylation sites are deleted or substituted, and by analysis of the ability of the SPR to desensitize when SPR cells express a GRK inhibitor.
For specific aim 2, the hypothesis that SPR resensitization requires dephosphorylation will be tested by examining the effects of specific cell-permeant protein phosphatase inhibitors and the hypothesis that receptor recycling back to the plasma membrane after agonist-induced endocytosis is also required for resensitization will be tested by examining the effects of agents that inhibit endosomal recycling. Finally, the ability of agonists, antagonists, and glucocorticoids to up- and down-regulate total cellular SPR levels and SPR mRNA levels will be assessed in order to begin to determine the mechanisms of cellular up- and down-regulation of substance P receptors. These studies will lead to insight into the normal mechanisms of SPR regulation and will suggest possible mechanisms of abnormal SPR regulation in inflammatory bowel disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050265-04
Application #
2900313
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
May, Michael K
Project Start
1996-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Vigna, Steven R (2016) Nicotine Inhibits Clostridium difficile Toxin A-Induced Colitis but Not Ileitis in Rats. Int J Inflam 2016:4705065
McVey, Douglas C; Vigna, Steven R (2005) The role of leukotriene B4 in Clostridium difficile toxin A-induced ileitis in rats. Gastroenterology 128:1306-16
McVey, Douglas C; Schmid, Patricia C; Schmid, Harald H O et al. (2003) Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther 304:713-22
Vigna, Steven R (2003) The role of the amino-terminal domain of tachykinins in neurokinin-1 receptor signaling and desensitization. Neuropeptides 37:30-5
Nathan, Jaimie D; Peng, Ruth Y; Wang, Yu et al. (2002) Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol 283:G938-46
McVey, D C; Vigna, S R (2001) The capsaicin VR1 receptor mediates substance P release in toxin A-induced enteritis in rats. Peptides 22:1439-46
Mantyh, C R; McVey, D C; Vigna, S R (2000) Extrinsic surgical denervation inhibits Clostridium difficile toxin A-induced enteritis in rats. Neurosci Lett 292:95-8
McVey, D C; Romac, J M; Clay, W C et al. (1999) Monitor peptide binding sites are expressed in the rat liver and small intestine. Peptides 20:457-64
Vigna, S R (1999) Phosphorylation and desensitization of neurokinin-1 receptor expressed in epithelial cells. J Neurochem 73:1925-32
Mantyh, C R; Pappas, T N; Lapp, J A et al. (1996) Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. Gastroenterology 111:1272-80

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