Recent research that we have carried out provides evidence for muscarinic-induced activation of the voltage-dependent Na+- channels in neurons in the central nervous system. In addition, there is evidence for depolarization-induced activation of Go proteins in neuronal cells and in cardiac myocytes, which results in depolarization induced interconversion of muscarinic receptors from their high affinity state to low affinity state. Go proteins are the most abundant G-protein in the central nervous system and in cardiac atria. Yet their physiological roles are not defined.
On the basis of these findings, we suggest that muscarinic receptors, the voltage-dependent Na+- channels and Go proteins act in a possible feedback mechanism producing continuous alternating changes in membrane potential from depolarization to hyperpolarization, which might underlie the autonomic repetitive firing in pacemaker cells.
In our research we are examining this hypothesis in rat cardiac myocytes by employing a combination of biochemical and electrophysiological methods. These include in-situ photoaffinity labeling of activated G-proteins, modification of Na+- channels, crosslinking of membrane proteins at resting potential and during membrane depolarization, and single channel current measurements induced by muscarinic stimulation.
The main goal of this research is to uncover the molecular basis underlying a signaling mechanism that consists of depolarization-induced, Go protein dependent modulations of cellular functions in excitable cells. Voltage dependent activation of Go protein would imply voltage-dependent modulation of their coupled patterns, constituting a mechanism whereby signal transduction patterns, triggered by receptor stimulation, are modified by membrane potential. Provided that basal concentration of transmitters are sufficient to produce the proposed interaction between ion channels, Go protein and receptors, the proposed voltage-induced changes in receptors signaling provide a novel mode of signal transmission modulation, which may underlie long term potentiation in synapses and repetitive firing in pacemakers.
