Fig. 10.

Model of NO-mediated inhibition of purine release in the colon. A: in human and wild-type mouse colon, propagation of action potentials (APs) into nerve varicosities of enteric inhibitory motor neurons stimulates release of NO that is produced from l-arginine (l-arg) via Nos1. Released NO stimulates postjunctional interstitial cells of Cajal (ICC) by binding to soluble guanylyl cyclase (sGC), which activates cGMP-dependent kinase I (PKG). Responses produced in ICC are propagated to smooth muscle cells (SMC) via gap junctions (GJ). NO also stimulates sGC (and possibly PKG) presynaptically in neurons to inhibit release of purines (PUR) from nerve varicosities (this study) and thus likely reduces purinergic responses in postjunctional PDGFRα⁺ cells. NO-induced release of NO from ICC (52) may also contribute to prejunctional sGC activation and inhibition of purine release (dashed arrows). Regulation of purine release by NO would limit the amounts of inhibitory neurotransmitters that are released into the neuroeffector junction (NEJ) and prevent overinhibition of colonic muscles during motor neuron activation. B: W/W^v mice have reduced colonic ICC and reduced expression of Nos1 resulting in decreased extracellular amounts of NO during AP firing and reduced sGC-mediated inhibition of purine release from nerve varicosities. Enhanced purine release and purine signaling via P2Y1 receptors (P2Y1R) on PDGFRα⁺ cells allows inhibitory motor responses to occur in the absence of ICC in W/W^v colons. PDGFRα⁺cells, platelet-derived growth factor receptor-α-positive cells.