G protein-gated K+ channels and inhibitory signaling

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DESCRIPTION: The long-term goal of my research is to understand how G protein-gated potassium channels (GIRK or KG channels) contribute to inhibitory signaling throughout the central nervous system, and how the cellular consequences of KG function translate into the establishment or modification of complex behaviors such as pain perception, addiction, and learning and memory. KG channels are formed by heteromultimeric assembly of members of the GIRK channel subunit family. The four mammalian GIRK subunits are distributed throughout the central nervous system, heart, pancreas, and testis. While the importance of neurotransmitter activation of KG channels to cardiac function is well understood, little is known regarding their contribution to inhibitory signaling and behavioral modification in the central nervous system. The work detailed in this proposal seeks to reveal how KG channels work in concert with other G protein-coupled effectors to elicit synaptic inhibition in the brain. First, however, considerable effort will be devoted to delineating precisely where each GIRK subunit is expressed in the brain. GIRK mRNAs will be localized in the mouse central nervous system by in situ hybridization. A novel transgenic strategy will be used to complement and extend the localization studies by revealing the distribution of the GIRK3 subunit proteins at the subcellular level. In addition, potential molecular mechanisms underlying their distribution will be explored. We will also evaluate the contribution of KG channels and other ion currents to the acute and chronic effects of opiates in the locus coeruleus. Currently, there is disagreement in the field concerning the contribution of KG to the acute effects of opiates in the locus coeruleus. In addition, our understanding of the mechanisms underlying the chronic effects of opiate administration (tolerance) is incomplete. Mice lacking KG in the locus coeruleus will be used to address these gaps in our knowledge. Completion of this work will constitute a first step toward a comprehensive understanding of KG regulation by neurotransmitters in the central nervous system. In addition, it will provide a basis for evaluating the impact of this particular ion channel class on a variety of behaviors at the cellular and whole-animal levels.