ACTION-POTENTIAL GENERATION, KIT RECEPTOR IMMUNOHISTOCHEMISTRY AND MORPHOLOGY OF STEEL-DICKIE (S1 S1(D)) MUTANT MOUSE SMALL-INTESTINE/

In contrast to wild-type mice, homozygotes with mutations of the W loc us do not express the functional Kit receptor and are severely deficie nt in the Auerbach's plexus (AP)-associated subtype of interstitial ce lls of Cajal (ICC-AP). With a morphologically intact neural and muscul ar structure, the absence in these mutants of both small-intestinal sl ow waves and ICC-AP constitutes strong evidence for a key role of ICC- AP as pacemaker cells. In steel-Dickie mutant mice (S1/S1(d)), the gen e coding for the Kit ligand (stem cell factor) is defective. We examin ed S1/S1(d) mutants and controls with intracellular microelectrode tec hniques, combined with light and electron microscopy. The absence of t he normal Kit ligand (S1/S1(d) mice) had very similar effects as the a bsence of the Kit receptor in viable mice, mutated at the White spotti ng, W locus (W/W-v mice), in that neither slow waves, nor Kit receptor immunoreactivity in the region of Auerbach's plexus nor ICC-AP were p resent in the small intestine. In the S1/S1(d) mouse, the smooth muscl e cells generated action potentials at variable frequencies from a dep olarized cell membrane of -40 to -55 mV. Increasing excitability by K channel blockers created many different patterns of action potential g eneration and the frequency increased from similar to 16 cpm to 66 cpm . This was in sharp contrast to control mice where action potentials w ere always restricted to the plateau phase of the slow waves and the s low wave frequency remained constant at similar to 39 cpm. Our data pr ovide further strong support for the identification of ICC-AP as small -intestinal pacemaker cells. In addition, they provide a basis for the understanding of intestinal motor function without pacemaker activity .