INTERSTITIAL-CELLS OF CAJAL MEDIATE INHIBITORY NEUROTRANSMISSION IN THE STOMACH

The structural relationships between interstitial cells of Cajal (ICC) , varicose nerve fibers, and smooth muscle cells in the gastrointestin al tract have led to the suggestion that ICC may be involved in or med iate enteric neurotransmission. We characterized the distribution of I CC in the murine stomach and found two distinct classes on the basis o f morphology and immunoreactivity to antibodies against c-Kit receptor s. ICC with multiple processes formed a network in the myenteric plexu s region from corpus to pylorus. Spindle-shaped ICC were found within the circular and longitudinal muscle layers (IC-IM) throughout the sto mach. The density of these cells was greatest in the proximal stomach. IC-IM ran along nerve fibers and were closely associated with nerve t erminals and adjacent smooth muscle cells. IC-IM failed to develop in mice with mutations in c-kit. Therefore, we used W/W-V mutants to test whether IC-IM mediate neural inputs in muscles of the gastric fundus. The distribution of inhibitory nerves in the stomachs of c-kit mutant s was normal, but NO-dependent inhibitory neuroregulation was greatly reduced. Smooth muscle tissues of W/W-V mutants relaxed in response to exogenous sodium nitroprusside, but the membrane potential effects of sodium nitroprusside were attenuated. These data suggest that IC-IM p lay a critical serial role in NO-dependent neurotransmission: the cell ular mechanism(s) responsible for transducing NO into electrical respo nses may be expressed in IC-IM. Loss of these cells causes loss of ele ctrical responsiveness and greatly reduces responses to nitrergic nerv e stimulation.