Membrane-delimited Modulation of Ionotropic Glutamate Receptors by Metabotropic Glutamate Receptors In the brain, the major excitatory neurotransmitter released by nerve terminals is glutamate. Glutamate can act on two types of proteins or receptors on the cell membrane: ionotropic glutamate receptors (or NMDA, AMPA/kainate receptors categorized according to specific agonists) and metabotropic glutamate receptors (mGluRs). NMDA and AMPA/kainate receptors are associated with ion permeable channels while mGluRs affect several intracellular signal systems; these two receptor families play critical roles in neurotransmission and synaptic plasticity, as well as in neuronal cell death (excitotoxicity). The proposed investigation will test the hypothesis that selective activation of mGluR subtypes 1/5 can suppress NMDA receptor activities by a mechanism involving a G protein that acts independently of diffusible second messengers. This type of ion channel modulation has been called membrane-delimited modulation, because it can be observed in small membrane pieces excised from intact cells. It is proposed that this membrane-delimited modulation of ionotropic glutamate receptors may provide a unique way of local regulation of synaptic transmission and excitotoxicity. The investigators will characterize the membrane-delimited modulation of NMDA and AMPA/kainate receptors by specific mGluRs and study the crucial mediating role of G proteins and their subunits. Ion channel activities will be examined using whole-cell and single-channel recordings in cultured cortical, hippocampal neurons, and glutamate-receptor-transfected HEK293 cells. Three specific aims will be investigated: 1) Membrane-delimited modulation of ionotropic glutamate receptors by specific mGluRs 2) Effect of mGluR activation on ionotropic glutamate receptor single channel currents 3) Role of G proteins in the mGluR-induced membrane-delimited modulation of ionotropic glutamate receptors. By accomplishing these aims, scientist will be able to understand better how those two types of glutamate receptors can communicate after concurrent stimulation by the neurotransmitter glutamate.
