Nitric oxide (NO) is an important inhibitory neurotransmitter for the gastrointestinal smooth muscles. As a neurotransmitter, NO plays a key role in peristalsis and physiological relaxation of the sphincters and thus facilitates transport of food through the gastrointestinal tract. Loss of NO-related neurotransmission has been shown to cause diseases causing difficulty in swallowing, gastric stasis, dyspepsia, intestinal stasis and constipation. Defective NO neurotransmission is also implicated in diabetic gastroparesis and functional disorders of the gut such as irritable bowel syndrome and spasm of biliary and pancreatic sphincters. Nitric oxide is uniquely different from other classical neurotransmitters. Unlike the classical neurotransmitters, NO is a highly diffusible gas that is produced de novo on demand from Ca-CaM dependent activation of nNOS. However, regulation of NO generation and nitrergic neurotransmission is not well understood. We have recently shown that isolated nitrergic varicosities from mice gut contain inactive and active pools of nNOS. Dynamic regulation of the catalytically active nNOS1 is responsible for regulation of nitrergic neurotransmission. Overall purpose of the proposed studies is to extend our studies of regulation of catalytically active nNOS in the nitrergic varicosities and determine how nNOS is transported to the membrane, attached there and regulated to produce NO. We will use this information to identify abnormities in the steps that may impair nitrergic neurotransmission. These studies will help define pathophysiology of impaired nitrergic neurotransmission that have no anatomical evidence of loss or damage to nitrergic nerves. There are four specific aims: 1) To examine the role of PIN/LC8 and myosin Va in targeting nNOS to varicosity membrane and to investigate nitrergic neurotransmission in mice lacking myosin Va. 2) To examine the role of PSD proteins in membrane association of nNOS1 dimer and to investigate nitrergic neurotransmission with depalmitoylation of PSD and in mice lacking PSD 95. 3) To investigate the clustering of nNOS-PSD complex with N-type calcium channels and the enzymes that dephosphorylate or phosphorylate nNOS and to investigate the effects of inhibitors of these enzymes on nitrergic neurotransmission. 4) To investigate the mechanism of reduced inhibitory neurotransmission in an animal model of diabetes mellitus (NOD mice).

Public Health Relevance

Gastrointestinal motility disorders result in a variety of diseases that cause difficulty in swallowing, heartburn, dyspepsia, constipation and chronic abdominal pain. This proposal is to understand how these disorders are caused and how better treatments for these disorders can be developed.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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Harvard University
Internal Medicine/Medicine
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United States
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Chaudhury, Arun; Cristofaro, Vivian; Carew, Josephine A et al. (2014) Myosin Va plays a role in nitrergic smooth muscle relaxation in gastric fundus and corpora cavernosa of penis. PLoS One 9:e86778
Goyal, R K; Sullivan, M P; Chaudhury, A (2013) Progress in understanding of inhibitory purinergic neuromuscular transmission in the gut. Neurogastroenterol Motil 25:203-7
Goyal, Raj K; Chaudhury, Arun (2013) Structure activity relationship of synaptic and junctional neurotransmission. Auton Neurosci 176:11-31
He, Xue-Dao; Goyal, Raj K (2012) CaMKII inhibition hyperpolarizes membrane and blocks nitrergic IJP by closing a Cl(-) conductance in intestinal smooth muscle. Am J Physiol Gastrointest Liver Physiol 303:G240-6
Chaudhury, Arun; He, Xue-Dao; Goyal, Raj K (2012) Role of myosin Va in purinergic vesicular neurotransmission in the gut. Am J Physiol Gastrointest Liver Physiol 302:G598-607
Chaudhury, Arun; He, Xue-Dao; Goyal, Raj K (2011) Myosin Va plays a key role in nitrergic neurotransmission by transporting nNOSýý to enteric varicosity membrane. Am J Physiol Gastrointest Liver Physiol 301:G498-507
Goyal, Raj K (2011) Evidence for ?-nicotinamide adenine dinucleotide as a purinergic, inhibitory neurotransmitter in doubt. Gastroenterology 141:e27; author reply e27-8
Goyal, Raj K; Chaudhury, Arun (2010) Mounting evidence against the role of ICC in neurotransmission to smooth muscle in the gut. Am J Physiol Gastrointest Liver Physiol 298:G10-3
Goyal, Raj K; Chaudhury, Arun (2010) Pathogenesis of achalasia: lessons from mutant mice. Gastroenterology 139:1086-90
Chaudhury, Arun; He, Xue-Dao; Goyal, Raj K (2009) Role of PSD95 in membrane association and catalytic activity of nNOSalpha in nitrergic varicosities in mice gut. Am J Physiol Gastrointest Liver Physiol 297:G806-13

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