Protease-activated receptors modulate excitability of murine colonic smooth muscles by differential effects on interstitial cells

摘要

Key points Activation of protease-activated receptors (PAR) regulates gastrointestinal (GI) motility but little is known about the cells and mechanisms in GI muscles responsible for PAR responses. Using mouse cells, we found high levels of F2r and F2rl1 PAR-encoding genes expressed in purified platelet-derived growth factor -positive (PDGFR(+)) cells in comparison to other cells in colonic muscles. PAR1 and PAR2 agonists caused transient hyperpolarization and relaxation of colonic muscles, with relaxation responses followed by excitation. The inhibitory phase was inhibited by apamin and mediated by activation of small conductance calcium-activated potassium channels in PDGFR(+) cells. The excitatory response resulted largely from activation of a chloride conductance in interstitial cells of Cajal; small amplitude inward currents were generated in smooth muscle cells by PAR activation, but these responses were too small to be resolved in intact muscles. PAR receptor responses are integrated responses generated by cells of the smooth muscle, interstitial cells of Cajal and PDGFR(+) cells (SIP syncytium).