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Interstitial cells of Cajal (ICC) regulate smooth muscle excitability and motility in the gastrointestinal (GI) tract. ICC in the deep muscular plexus (ICC-DMP) of the small intestine are aligned closely with varicosities of enteric motor neurons and thought to transduce neural responses. ICC-DMP generate Ca 2+ transients that activate Ca 2+ activated Cl - channels and generate electrophysiological responses. We tested the hypothesis that excitatory neurotransmitters regulate Ca 2+ transients in ICC-DMP as a means of regulating intestinal muscles. High-resolution confocal microscopy was used to image Ca 2+ transients in ICC-DMP within murine small intestinal muscles with cell-specific expression of GCaMP3. Intrinsic nerves were stimulated by electrical field stimulation (EFS). ICC-DMP exhibited ongoing Ca 2+ transients before stimuli were applied. EFS caused initial suppression of Ca 2+ transients, followed by escape during sustained stimulation, and large increases in Ca 2+ transients after cessation of stimulation. Basal Ca 2+ activity and the excitatory phases of Ca 2+ responses to EFS were inhibited by atropine and neurokinin 1 receptor (NK1) antagonists, but not by NK2 receptor antagonists. Exogenous ACh and substance P (SP) increased Ca 2+ transients, atropine and NK1 antagonists decreased Ca 2+ transients. Neurokinins appear to be released spontaneously (tonic excitation) in small intestinal muscles and are the dominant excitatory neurotransmitters. Subcellular regulation of Ca 2+ release events in ICC-DMP may be a means by which excitatory neurotransmission organizes intestinal motility patterns.