Zholos O. Membrane and intracellular mechanisms of the M-cholinergic activation of smooth muscle cells from the small intestine

The cholinergic excitatory mechanisms in intestinal smooth muscle cells were studied using patch-clamp techniques and flash photolysis of various "caged" substances. Important species- and age-related differences in the expression and properties of various ion channels have been found in non-stimulated cells. Ionic currents in myenteric neurones have also been characterised. M2 receptor-mediated membrane depolarization due to cationic channel opening evokes Ca2+ entry via L-type channels which initiates Ca2+-induced Ca2+ release from the intracellular store. This produces an additional Ca2+-dependent activation of the cationic channels and an initial augmentation of the IP3-induced Ca2+ release. Developing depolarization further activates cationic channels. Protective processes and deactivation involve GTP-dependent desensitization of the cationic conductance, Ca2+ current inhibition (an M2 effect), delayed long-lasting Ca2+-dependent inactivation of the IP3 receptors and hyperpolarizing IK(Ca) activat ion. The voltage range of cationic channel activation is dynamically altered depending on the level of activated G-proteins. On the basis of these observations a mathematical model of the muscarinic receptor-gated cationic current generation is presented which explains its kinetics and voltage-dependent properties.