Nitric oxide and its role as a non-adrenergic, non-cholinergic inhibitory neurotransmitter in the gastrointestinal tract.

NO is a neurotransmitter released from enteric inhibitory neurons and responsible for modulating gastrointestinal (GI) motor behaviour. Enteric neurons express nNOS (NOS1) that associates with membranes of nerve varicosities. NO released from neurons binds to soluble guanylate cyclase in post-junctional cells to generate cGMP. cGMP-dependent protein kinase type 1 (PKG1) is a major mediator but perhaps not the only pathway involved in cGMP-mediated effects in GI muscles based on gene deletion studies. NOS1+ neurons form close contacts with smooth muscle cells (SMCs), interstitial cells of Cajal (ICC) and PDGFRα+ cells, and these cells are electrically coupled (SIP syncytium). Cell-specific gene deletion studies have shown that nitrergic responses are due to mechanisms in SMCs and ICC. Controversy exists about the ion channels and other post-junctional mechanisms that mediate nitrergic responses in GI muscles. Reduced nNOS expression in enteric inhibitory motor neurons and/or reduced connectivity between nNOS+ neurons and the SIP syncytium appear to be responsible for motor defects that develop in diabetes. An overproduction of NO in some inflammatory conditions also impairs normal GI motor activity. This review summarizes recent findings regarding the role of NO as an enteric inhibitory neurotransmitter.