A Role of c-kit tyrosinekinase of physiological development of the gastrointestinal pacemaker activity

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As to origin of electrical and mechanical rhythmicity in the gastrointestinal tract, a class of specialized cells, often referred to as interstitial cells (IC) have been suggested to serve as pacemaker cells However, the function of ICs has been difficult to investigate in intact muscles because of the structural complexities of GI muscle and the IC network. We took a different approach to explore function of the ICs in the intestine. Results are as follows, 1) A certain type of cells in smooth muscle layrs of developing gastrointestinal tract in the mouse expresses Kit-gene which is a proto-oncogene encoding a receptor tyrosine in PDGF/CSF-I receptor family and in vitro injection of a neutralizing antibody (ACK2) for the proto-oncogene product, Kit protein, during the first few days after birth reduced the number of the Kit-expressing cells, which was accompanied by impairment of development of normal rhythmic mechanical activity in the mouse intestine, 2) ACK2 specifically labels int … More erstitial cells (ICs) in the mouse GI tracts, and ACK2-treatment induces a loss of electrical slow wave activity and depolarization of the membranes of smooth muscle cells, 3) we have succeeded in isolating ICs in primary culture of the mice small intestine and recorded spontaneously active electrical currents from these primary cultured ICs, 4) Both of the voltage-sensitive Na^+ and Ca^<2+> currents were not observed clearly in the all c-kit ^+ cells tested, but the rhythmic fluctuation of membrane voltage was observed under the current-clamp condition, where only Cl^- permeates, 5) In the ileum of neonates on the day of birth (day 0 pp) which did not show any spontaneous contractile activity, ACh (>10^<-8>M) induced a dose-related sustained contraction, but the contractile responses to ACh declined in sensitivity each day after birth in the control mice, while ileum of ACK2-treated animals did not show a decrease in the sensitivity to ACh as well as prostaglandin E1 and F2a. These observations indicate that the kit--signaling pathway is important in the development of ICs as pacemaker cells in the intestinal tract. Impairment of development of the IC network would not only affect GI motility but also affect pharmacological characteristics of the ileac smooth muscle. Less