title: Adenosine 5-diphosphate-ribose is a neural regulator in primate and murine large intestine along with β-NAD(+).
abstract: Adenosine 5′-triphosphate (ATP) has long been considered to be the purine inhibitory neurotransmitter in gastrointestinal (GI) muscles, but recent studies indicate that another purine nucleotide, β-nicotinamide adenine dinucleotide (β-NAD(+)), meets pre- and postsynaptic criteria for a neurotransmitter better than ATP in primate and murine colons. Using a small-volume superfusion assay and HPLC with fluorescence detection and intracellular microelectrode techniques we compared β-NAD(+) and ATP metabolism and postjunctional effects of the primary extracellular metabolites of β-NAD(+) and ATP, namely ADP-ribose (ADPR) and ADP in colonic muscles from cynomolgus monkeys and wild-type (CD38(+/+)) and CD38(−/−) mice. ADPR and ADP caused membrane hyperpolarization that, like nerve-evoked inhibitory junctional potentials (IJPs), were inhibited by apamin. IJPs and hyperpolarization responses to ADPR, but not ADP, were inhibited by the P2Y1 receptor antagonist (1R,2S,4S,5S)-4-[2-iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (MRS2500). Degradation of β-NAD(+) and ADPR was greater per unit mass in muscles containing only nerve processes than in muscles also containing myenteric ganglia. Thus, mechanisms for generation of ADPR from β-NAD(+) and for termination of the action of ADPR are likely to be present near sites of neurotransmitter release. Degradation of β-NAD(+) to ADPR and other metabolites appears to be mediated by pathways besides CD38, the main NAD-glycohydrolase in mammals. Degradation of β-NAD(+) and ATP were equal in colon. ADPR like its precursor, β-NAD(+), mimicked the effects of the endogenous purine neurotransmitter in primate and murine colons. Taken together, our observations support a novel hypothesis in which multiple purines contribute to enteric inhibitory regulation of gastrointestinal motility.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557-0575, USA.
authors.forename: Leonie
authors.initials: L
authors.lastname: Durnin
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Sean M
authors.initials: SM
authors.lastname: Ward
authors.forename: Kenton M
authors.initials: KM
authors.lastname: Sanders
authors.forename: Violeta N
authors.initials: VN
authors.lastname: Mutafova-Yambolieva
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000187:drug effects; D008252:Macaca fascicularis / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011687:Purines / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018377:Neurotransmitter Agents; D058921:Purinergic P2Y Receptor Antagonists; D011687:Purines; D058472:Receptors, Purinergic P2Y1; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C030985:purine