A number of motility disorders are believed to be caused by defects in the neural control of the gastrointestinal (GI) tract. However, the underlying pathophysiology remains largely undefined and often the treatment is ineffectively targeted. Our long-term goal is to develop methods for the prevention and treatment of conditions qualified as "neuropathies" based on understanding of the inhibitory purinergic signaling in the gut. The central hypothesis of this proposal is that beta-nicotinamide adenine dinucleotide ((3-NAD) is a novel inhibitory neurotransmitter in the GI tract. Particularly, we hypothesize that (3-NAD is stored in synaptic vesicles, is released upon action potential firing, activates P2Y purinergic receptors and apamin-sensitive small conductance Ca2+-activated potassium (SK) channels on either interstitial cells of Cajal (ICC), smooth muscle cells (SMC) or fibroblast-like cells (FLC), causes membrane hyperpolarization and smooth muscle relaxation, and is removed by CD38- and CD157-mediated metabolism and by uptake in nerve varicosities. The work, carried out with colon preparations from humans, non-human primates, and mice, will: (i) determine the cell types that are the primary source of release of (3-NAD and ATP during EPS of enteric nerves (Aim 1), (ii) examine whether the expression, distribution, and function of vesicular nucleotide transporter (VNUT) is consistent with the role of (3-NAD as an inhibitory motor neurotransmitter in GI muscles (Aim 2), (iii) determine the primary postjunctional targets of PNAD action (Aim 3), and (iv) examine the major mechanisms of removal of (3-NAD (i.e., enzymatic degradation or neuronal uptake), and hence of terminating its neurotransmitter actions (Aim 4). We will examine overflow of purine neurotransmitters and their metabolites using high performance liquid chromatography (HPLC) techniques along with immunohistochemistry, protein biochemistry, molecular biology techniques, electron microscopy, flow cystometry analysis, electrophysiology, and functional approaches to better understand the role of p-NAD and other purines as putative neurotransmitters. This research has the potential to fundamentally advance our understanding of enteric purinergic signaling, and could have important implications for developing novel therapeutic strategies for GI motility disorders based on defects of neural control of the GI muscles.

Public Health Relevance

Millions of American patients suffer from conditions of inadequately regulated gastrointestinal functions including constipation, diarrhea, irritable bowel disorder, and diabetic enteropathy, which may have detrimental effects on quality of life. The cause of many of these disorders is not precisely known. The results from the present proposal may suggest new strategies for interrupting or preventing pathological conditions associated with gut dysfunction specifically related to abnormal neural regulation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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University of Nevada Reno
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Sanders, Kenton M; Salter, Anna K; Hennig, Grant W et al. (2014) Responses to enteric motor neurons in the gastric fundus of mice with reduced intramuscular interstitial cells of cajal. J Neurogastroenterol Motil 20:171-84
Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don et al. (2014) Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am J Physiol Cell Physiol 306:C705-13
McCann, Conor J; Hwang, Sung-Jin; Hennig, Grant W et al. (2014) Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal. J Neurogastroenterol Motil 20:326-37
Durnin, Leonie; Hwang, Sung Jin; Kurahashi, Masaaki et al. (2014) Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut. Proc Natl Acad Sci U S A 111:15821-6
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Drumm, Bernard T; Koh, Sang Don; Andersson, Karl-Erik et al. (2014) Calcium signalling in Cajal-like interstitial cells of the lower urinary tract. Nat Rev Urol 11:555-64
Mutafova-Yambolieva, Violeta N; Durnin, Leonie (2014) The purinergic neurotransmitter revisited: a single substance or multiple players? Pharmacol Ther 144:162-91
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Kurahashi, Masaaki; Nakano, Yasuko; Peri, Lauren E et al. (2013) A novel population of subepithelial platelet-derived growth factor receptor *-positive cells in the mouse and human colon. Am J Physiol Gastrointest Liver Physiol 304:G823-34
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