ICCs appear to be involved in neurotransmission to GI smooth musclemuscle (Ward & Sanders, 2001; Hirst & Edwards, 2004; Sivarao et al. 2001). To determine whether this is neurotransmitter specific, LES CSM in W/W^v wild-type (+/+) and mutant (−/−) mice were studied using intracellular recordings in vitro. LES strips were prepared after mice of either sex were humanely killed. In the presence of nifedipine, guanethidine and substance P, resting membrane potential (MP) of LES was −44.5±2.3 mV (n=6) in wild-type vs. −51.6±1.6 mV in mutant mice (n=15, P〈0.05). In wild-type mice nerve stimulation induced a biphasic IJP consisting of an initial fast IJP (fIJP) with amplitude of 7.7±2.1 mV and duration of 644±97 ms followed by a second slow IJP (sIJP) with amplitude of 1.9±0.7 mV and duration of 11048±1779 ms (n=6). The fIJP in mutant mice was no different than wild-type, but the sIJP was impaired (amplitude 0.1 ±0.5 mV; n=15, P〈0.05). Atropine increased the aplitude of both IJP components to 10.9±1.7 mV and 4.2±0.7 mV in wild-type (n=6, P〈0.05), and to 8.2±1.6 mV (n=15, P〉0.05) and 1.5±0.4 mV (n=15, P〈0.05) in mutant mice, respectively. Concomitant application of apamin in wild-type mice depolarized MP to −37.3±1.9 mV and decreased the amplitude of the fIJP to 7.3±2.0 mV (n=5, P〈0.05), but had no effect on the sIJP. In mutant mice, apamin depolarized MP to −43.4±1.8 mV and decreased the fIJP amplitude to 3.0±1.3 mV (n=14, P〈0.05), but had no effect on sIJP amplitude. Subsequent application of L-NAME markedly inhibited the biphasic IJP amplitudes to 1.3±0.5 mV and 0.1±0.1 mV, respectively, in wild-type mice (n=4, P〈0.05). However, in mutant mice L-NAME did not significantly suppress the apamin-resistant component of the fIJP (n=12, P〉0.05) but completely eradicted the sIJP (n=12, P〈0.05). Moreover, application of caffeine hyperpolarized MP to −52.8±1.7 mV, inhibited the fIJP to 6.6±1.6 mV, and completely abolished the sIJP in wild-type mice (n=6, P〈0.05). In contrast, caffeine depolarized MP to −42.4±1.8 mV and abolished the sIJP (n=9, P〈0.05), but did not affect the fIJP (n=9, P〉0.05) in mutant mice. These data suggest that purinergic and cholinergic neurotransmission is preserved whereas nitrergic neurotransmission is impaired in LES CSM of W/W^v mutant mice. The impaired nitrergic neurotransmission is associated with evidence for dysfunction of sarcoplasmic reticulum in mutant mice.