The Enteric Nervous System

Sanders, Kenton M, Kenton M. Sanders, Sanders, Kenton M.

The idea of an inhibitory innervation in the gut came from Geoff Burnstock's group at the University of Melbourne in the 1960s. Being resistant to antagonists of norepinephrine and acetylcholine, enteric inhibitory neurotransmission became known as non-cholinergic, non-adrenergic (NANC) neurotransmission. ATP (or a closely related nucleotide) was proposed as the inhibitory neurotransmitter based on release of purines during nerve stimulation and similarities between responses to ATP and transmural nerve stimulation in several gut preparations. Apamin was found to block purinergic responses, providing evidence that small-conductance Ca(2+)-activated K(+) (SK) channels were responsible for inhibitory junction potentials (IJPs). Actually the IJPs in GI muscles are composed of multiple components, and later studies discovered nitric oxide (NO) to be the other major mediator of NANC inhibitory neurotransmission. The purinergic component of enteric inhibitory neurotransmission is mediated by P2Y1 receptors, and this component is absent in P2Y1(-/-) mice. The criteria for a neurotransmitter are better met by β-nicotinamide adenine dinucleotide (β-NAD) or its immediate metabolite ADP-ribose (ADPR) than by ATP. The cells mediating post-junctional responses have been identified. In addition to smooth muscle cells, two classes of interstitial cells express receptors and effectors for NANC neurotransmitters and are electrically coupled to smooth muscle cells. This integrated structure has been named the SIP syncytium. Interstitial cells of Cajal are involved in transduction of cholinergic and nitrergic inputs to GI muscles, and PDGFRα(+) cells mediate purinergic effects. This short symposium report summarizes major historical points of interest and some of the more recent findings related to enteric inhibitory neurotransmission.