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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Baker, Salah A; Drumm, Bernard T; Saur, Dieter et al. (2016) Spontaneous Ca(2+) transients in interstitial cells of Cajal located within the deep muscular plexus of the murine small intestine. J Physiol 594:3317-38
Durnin, Leonie; Hayoz, Sebastien; Corrigan, Robert D et al. (2016) Urothelial purine release during filling of murine and primate bladders. Am J Physiol Renal Physiol 311:F708-F716
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe. J Physiol 594:1515
Hwang, Sung Jin; Basma, Naseer; Sanders, Kenton M et al. (2016) Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. Br J Pharmacol 173:1339-49
Durnin, L; Moreland, N; Lees, A et al. (2016) A commonly used ecto-ATPase inhibitor, ARL-67156, blocks degradation of ADP more than the degradation of ATP in murine colon. Neurogastroenterol Motil 28:1370-81
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut. J Physiol 594:1507-9
Sanders, Kenton M (2015) New Molecular Tools to Investigate the Development and Functions of Interstitial Cells of Cajal in the GI Tract. Gastroenterology 149:283-6
Peri, Lauren E; Koh, Byoung H; Ward, Grace K et al. (2015) A novel class of interstitial cells in the mouse and monkey female reproductive tracts. Biol Reprod 92:102
Baker, Salah A; Hennig, Grant W; Ward, Sean M et al. (2015) Temporal sequence of activation of cells involved in purinergic neurotransmission in the colon. J Physiol 593:1945-63
Zhu, Mei Hong; Sung, Tae Sik; O'Driscoll, Kate et al. (2015) Intracellular Ca(2+) release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal. Am J Physiol Cell Physiol 308:C608-20

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