The nervous system transmits information from cell to cell through electrical signals, called action potentials. An individual neuron receives hundreds of neurotransmitter inputs, integrates these into a firing pattern, and releases its own complement of neurotransmitters onto cells it stimulates or inhibits. The rate of firing of action potential is controlled by ion channels, some of which are directly, or indirectly, modulated by transmitters. In this proposal, we will determine the mechanism of action of one class of transmitter-gated ion channels on central nervous system activity. Muscarinic receptors are widespread in central nervous tissue but their overall functions are poorly understood. At least five types of muscarinic receptors are linked through GTP binding proteins to various cellular effectors. The m2 and m4 muscarinic receptors release Gbetagamma subunits to directly activate inward rectifying K/+- selective channels. These channels are comprised of subunits of four types. Although the channels they form are tetramers of GIRK1 plus one of GIRK2,3, or 4 subtypes, the conductance and gating of these channels appear to be identical. We seek to understand how muscarinic m2/m4 receptor activation gates GIRK channels in the CNS, whether the channels act presynaptically to inhibit neurotransmitter release or postsynaptically to inhibit action potential firing, and to determine the role of these channels in the fine dendritic processes. The overall objective is to determine common mechanisms for m2/m4 mediated inhibition of neuronal firing in several areas of the brain.
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