ß-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 41; p. 16359
• Main Authors: Mutafova-Yambolieva, Violeta N, Hwang, Sung Jin, Hao, Xuemei, Chen, Hui, Zhu, Michael X, Wood, Jackie D, Ward, Sean M, Sanders, Kenton M
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 09.10.2007
• Subjects: Acids; Adenosine triphosphatase; Cells; Muscular system; Neurons
• ISSN: 0027-8424; 1091-6490

Peripheral inhibitory nerves are physiological regulators of the contractile behavior of visceral smooth muscles. One of the transmitters responsible for inhibitory neurotransmission has been reputed to be a purine, possibly ATP. However, the exact identity of this substance has never been verified. Here we show that β-nicotinamide adenine dinucleotide (β-NAD), an inhibitory neurotransmitter candidate, is released by stimulation of enteric nerves in gastrointestinal muscles, and the pharmacological profile of β-NAD mimics the endogenous neurotransmitter better than ATP. Levels of β-NAD in superfusates of muscles after nerve stimulation exceed ATP by at least 30-fold; unlike ATP, the release of β-NAD depends on the frequency of nerve stimulation. β-NAD is released from enteric neurons, and release was blocked by tetrodotoxin or ...-conotoxin OVIA. β-NAD is an agonist for P2Y1 receptors, as demonstrated by receptor-mediated responses in HEK293 cells expressing P2Y1 receptors. Exogenous β-NAD mimics the effects of the enteric inhibitory neurotransmitter. Responses to β-NAD and inhibitory junction potentials are blocked by the P2Y 1-selective antagonist, MRS2179, and the nonselective P2 receptor antagonists, pyridoxal phosphate 6-azophenyl-2',4'-disulfonic acid and suramin. Responses to ATP are not blocked by these P2Y receptor inhibitors. The expression of CD38 in gastrointestinal muscles, and specifically in interstitial cells of Cajal, provides a means of transmitter disposal after stimulation. β-NAD meets the traditional criteria for a neurotransmitter that contributes to enteric inhibitory regulation of visceral smooth muscles. (ProQuest: ... denotes formulae/symbols omitted.)