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.
| Tipps, Megan; Marron Fernandez de Velasco, Ezequiel; Schaeffer, Allee et al. (2018) Inhibition of Pyramidal Neurons in the Basal Amygdala Promotes Fear Learning. eNeuro 5: |
| Luján, Rafael; Aguado, Carolina; Ciruela, Francisco et al. (2018) Differential association of GABAB receptors with their effector ion channels in Purkinje cells. Brain Struct Funct 223:1565-1587 |
| Marron Fernandez de Velasco, Ezequiel; Carlblom, Nicholas; Xia, Zhilian et al. (2017) Suppression of inhibitory G protein signaling in forebrain pyramidal neurons triggers plasticity of glutamatergic neurotransmission in the nucleus accumbens core. Neuropharmacology 117:33-40 |
| McCall, Nora M; Kotecki, Lydia; Dominguez-Lopez, Sergio et al. (2017) Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice. Neuropsychopharmacology 42:707-715 |
| Marron Fernandez de Velasco, Ezequiel; Zhang, Lei; N Vo, Baovi et al. (2017) GIRK2 splice variants and neuronal G protein-gated K+ channels: implications for channel function and behavior. Sci Rep 7:1639 |
| Montandon, Gaspard; Ren, Jun; Victoria, Nicole C et al. (2016) G-protein-gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids. Anesthesiology 124:641-50 |
| Victoria, Nicole C; Marron Fernandez de Velasco, Ezequiel; Ostrovskaya, Olga et al. (2016) G Protein-Gated K+ Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning. Biol Psychiatry 80:796-806 |
| Marron Fernandez de Velasco, Ezequiel; McCall, Nora; Wickman, Kevin (2015) GIRK Channel Plasticity and Implications for Drug Addiction. Int Rev Neurobiol 123:201-38 |
| Herman, Melissa A; Sidhu, Harpreet; Stouffer, David G et al. (2015) GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. Proc Natl Acad Sci U S A 112:7091-6 |
| Slesinger, Paul A; Wickman, Kevin (2015) Preface. Int Rev Neurobiol 123:xi-xii |
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