Neuronal G protein-gated inwardly rectifying K+ (GIRK) channels mediate the postsynaptic inhibitory effect of many neurotransmitters and related drugs of abuse. The long-term goal of my research is to understand how GIRK channels shape behaviors associated with specific neurotransmitter signaling pathways. To accomplish this objective, we need to understand the functional implications of native GIRK channel diversity, and we need to develop the means to perturb GIRK channels with molecular precision. Accordingly, the goal of this proposal is to determine how subunit composition influences interactions between GIRK channels and related signaling molecules. Our working hypothesis is that subunit composition dictates interactions between GIRK channels and neuronal proteins that facilitate coupling with appropriate G protein-coupled receptors. The working hypothesis will be tested with cell biological, biochemical, electrophysiological, and behavioral experiments that examine the robust coupling between GIRK channels and the GABAB receptor. We will exploit the existence of a powerful set of mouse knockout lines and custom-derived antibodies to identify structural elements promoting robust functional interactions between GIRK2-containing channels and GABAB receptors (AIM #1), to determine how GIRK channel subunit composition influences interactions with endogenous neuronal proteins (AIM #2), and to examine how subunit composition influences the contribution of GIRK channels to the behavioral effects of GABAB receptor activation (AIM #3). While addressing issues related to GIRK channels and G protein signaling that have been refractory to standard recombinant approaches, the proposed research will also suggest novel points of intervention for the selective perturbation of signaling involving GABAB receptors and/or GIRK channels. In the context of GABAB-dependent signaling, such progress could translate into novel therapies for the treatment of epilepsy, pain, and addiction. Relevance to public health. All drugs used to treat human disease or distress produce both beneficial and untoward effects. The premise of the work presented in this application is that the beneficial effects of many drugs could be emphasized, or the negative effects suppressed, if we understood better the molecular mechanisms underlying the complex physiological and behavioral responses to drug administration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061933-10
Application #
7996648
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Asanuma, Chiiko
Project Start
2000-07-01
Project End
2012-01-31
Budget Start
2011-01-01
Budget End
2012-01-31
Support Year
10
Fiscal Year
2011
Total Cost
$276,309
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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
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
Marron Fernandez de Velasco, Ezequiel; Hearing, Matthew; Xia, Zhilian et al. (2015) Sex differences in GABA(B)R-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex. Neuropharmacology 95:353-60
Kotecki, Lydia; Hearing, Matthew; McCall, Nora M et al. (2015) GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner. J Neurosci 35:7131-42
Slesinger, Paul A; Wickman, Kevin (2015) Preface. Int Rev Neurobiol 123:xi-xii
Marron Fernandez de Velasco, Ezequiel; McCall, Nora; Wickman, Kevin (2015) GIRK Channel Plasticity and Implications for Drug Addiction. Int Rev Neurobiol 123:201-38
Wydeven, Nicole; Marron Fernandez de Velasco, Ezequiel; Du, Yu et al. (2014) Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297. Proc Natl Acad Sci U S A 111:10755-60
Lujan, Rafael; Marron Fernandez de Velasco, Ezequiel; Aguado, Carolina et al. (2014) New insights into the therapeutic potential of Girk channels. Trends Neurosci 37:20-9
Wydeven, Nicole; Posokhova, Ekaterina; Xia, Zhilian et al. (2014) RGS6, but not RGS4, is the dominant regulator of G protein signaling (RGS) modulator of the parasympathetic regulation of mouse heart rate. J Biol Chem 289:2440-9

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