The aim of this proposal is to characterize receptors for neuropeptides on muscle cells from human and guinea pig stomach and biliary tract, and to identify the signal transduction pathways to which the receptors are coupled. Cells from different regions of these organs will be examined to determine the existence of functional gradients intrinsic to muscle cells. The emphasis will be on characterization of receptor types for contractile neuropeptides of the tachykinin, opioid and bombesin families and for relaxant neuropeptides of the VIP/PHI family. Characterization will be facilitated by two new approaches: the first enables protection of specific receptor types with selective ligands resulting in enrichment of muscle cells from scarce human tissue and from discrete segments of the stomach and biliary tract. Substantial progress has been made in identifying the transduction pathways for contraction and relaxation: cytosolic free Ca2+ ([Ca2+]i), measured for the first time in human and guinea pig gastric muscle cells, was shown to be stoichiometrically related to net Ca2+ efflux and contraction; inositol 1,4,5-triphosphate (IP3) was shown to cause contraction and Ca2+ release from the intracellular pool used by agonists; and cAMP-dependent relaxation was shown to involve two Ca2+-dependent mechanisms. Studies on contractile neuropeptides will now focus on the kinetics and stoichiometry of membrane phophoinositides, mainly IP3 and its metabolic products, IP4, and their relation to Ca2+ release and uptake and myosin light chain phosphorylation. Studies on relaxation neuropeptides will focus on the mode of action of cAMP in relation to [Ca2+]i and myosin light chain phosphorylation. The properties of two myenteric neuropeptides, somatostatin and galanin, which have no direct contractile or relaxant effects, but which are coupled to modulatory pathways that converge on intracellular Ca2+, will be explored. Somatostatin was shown to inhibit VIP-induced relaxation via coupling to Gi, and galanin to augment relaxation hyperpolarization and opening of K+ channels. A dual coupling of opioid peptides to stimulation of [Ca2+]i and to inhibition of cAMP was also shown. The physiological importance of these novel modulatory and interactive pathways is underlined by the co-localization of VIP, galanin and opioid peptides in a majority of myenteric neurons supplying smooth muscle.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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Virginia Commonwealth University
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Mahavadi, Sunila; Grider, John R; Murthy, Karnam S (2018) Muscarinic m2 receptor-mediated actin polymerization via PI3 kinase ? and integrin-linked kinase in gastric smooth muscle. Neurogastroenterol Motil :e13495
Mahavadi, Sunila; Nalli, Ancy D; Wang, Hongxia et al. (2018) Regulation of gastric smooth muscle contraction via Ca2+-dependent and Ca2+-independent actin polymerization. PLoS One 13:e0209359
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Blakeney, Bryan A; Crowe, Molly S; Mahavadi, Sunila et al. (2018) Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway. Dig Dis Sci :
Parikh, Jay; Zemljic-Harpf, Alice; Fu, Johnny et al. (2017) Altered Penile Caveolin Expression in Diabetes: Potential Role in Erectile Dysfunction. J Sex Med 14:1177-1186
Nalli, Ancy D; Wang, Hongxia; Bhattacharya, Sayak et al. (2017) Inhibition of RhoA/Rho kinase pathway and smooth muscle contraction by hydrogen sulfide. Pharmacol Res Perspect 5:
Mahavadi, Sunila; Sriwai, Wimolpak; Manion, Olivia et al. (2017) Diabetes-induced oxidative stress mediates upregulation of RhoA/Rho kinase pathway and hypercontractility of gastric smooth muscle. PLoS One 12:e0178574
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Qian, Jie; Mummalaneni, Shobha K; Alkahtani, Reem M et al. (2016) Nicotine-Induced Effects on Nicotinic Acetylcholine Receptors (nAChRs), Ca2+ and Brain-Derived Neurotrophic Factor (BDNF) in STC-1 Cells. PLoS One 11:e0166565

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