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Research ArticleArticle

Conformational Dynamics of Kir3.1/Kir3.2 Channel Activation Via δ-Opioid Receptors

Melissa Richard-Lalonde, Karim Nagi, Nicolas Audet, Rory Sleno, Mohammad Amraei, Mireille Hogue, Gianfranco Balboni, Peter W. Schiller, Michel Bouvier, Terence E. Hébert and Graciela Pineyro
Molecular Pharmacology February 2013, 83 (2) 416-428; DOI: https://doi.org/10.1124/mol.112.081950
Melissa Richard-Lalonde
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Karim Nagi
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Nicolas Audet
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Rory Sleno
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Mohammad Amraei
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Mireille Hogue
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Gianfranco Balboni
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Peter W. Schiller
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Michel Bouvier
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Terence E. Hébert
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Graciela Pineyro
Centre de Recherche de l’Hôpital Sainte-Justine (M.R.-L., K.N., N.A., G.P.); Département de Pharmacologie (M.R.-L., K.N., N.A., G.P.), Département de Psychiatrie (G.P.), and Faculté de Médecine and Institut de Recherche en Immunologie et en Cancérologie (M.H., M.B.), Université de Montréal; Department of Pharmacology and Therapeutics, McGill University (R.S., T.E.H.); and the Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal (P.W.S.), Montréal, Québec, Canada, and the Department of Life and Environment Sciences, University of Cagliari, Italy (G.B.)
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Abstract

This study assessed how conformational information encoded by ligand binding to δ-opioid receptors (DORs) is transmitted to Kir3.1/Kir3.2 channels. Human embryonic kidney 293 cells were transfected with bioluminescence resonance energy transfer (BRET) donor/acceptor pairs that allowed us to evaluate independently reciprocal interactions among signaling partners. These and coimmunoprecipitation studies indicated that DORs, Gβγ, and Kir3 subunits constitutively interacted with one another. GαoA associated with DORs and Gβγ, but despite being part of the complex, no evidence of its direct association with the channel was obtained. DOR activation by different ligands left DOR-Kir3 interactions unmodified but modulated BRET between DOR-GαoA, DOR-Gβγ, GαoA-Gβγ, and Gβγ-Kir3 interfaces. Ligand-induced BRET changes assessing Gβγ-Kir3.1 subunit interaction 1) followed similar kinetics to those monitoring the GαoA-Gβγ interface, 2) displayed the same order of efficacy as those observed at the DOR-Gβγ interface, 3) were sensitive to pertussis toxin, and 4) were predictive of whether a ligand could evoke channel currents. Conformational changes at the Gβγ/Kir3 interface were lost when Kir3.1 subunits were replaced by a mutant lacking essential sites for Gβγ-mediated activation. Thus, conformational information encoded by agonist binding to the receptor is relayed to the channel via structural rearrangements that involve repositioning of Gβγ with respect to DORs, GαoA, and channel subunits. Further, the fact that BRET changes at the Gβγ-Kir3 interface are predictive of a ligand’s ability to induce channel currents points to these conformational biosensors as screening tools for identifying GPCR ligands that induce Kir3 channel activation.

Footnotes

  • This research was supported by grants from the Natural Sciences and Engineering Research Council of Canada [311997] (G.P.); the Canadian Institutes of Health Research (CIHR) [MOP 79432] (G.P.), [MOP 79354] (T.E.H.), and P.W.S. [MOP 89716] (P.W.S.); and the Consortium québécois sur la découverte du médicament (G.P., T.E.H., M.B.); and by National Institutes of Health [Grant DA004443] to (P.W.S.). T.E.H. holds a Chercheur National award from the Fonds de la Recherche en Santé du Québec. M.B. holds a Canada Research Chair in Cell Signalling and Molecular Pharmacology. R.S. holds a studentship from the McGill-CIHR Drug Development Training Program. K.N. holds a studentship from Ste-Justine Hospital Research Center.

  • dx.doi.org/10.1124/mol.112.081950.

  • Received August 19, 2012.
  • Accepted November 21, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (2)
Molecular Pharmacology
Vol. 83, Issue 2
1 Feb 2013
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Research ArticleArticle

Kir3.1//Kir3.2 Channel Activation by DORs

Melissa Richard-Lalonde, Karim Nagi, Nicolas Audet, Rory Sleno, Mohammad Amraei, Mireille Hogue, Gianfranco Balboni, Peter W. Schiller, Michel Bouvier, Terence E. Hébert and Graciela Pineyro
Molecular Pharmacology February 1, 2013, 83 (2) 416-428; DOI: https://doi.org/10.1124/mol.112.081950

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Research ArticleArticle

Kir3.1//Kir3.2 Channel Activation by DORs

Melissa Richard-Lalonde, Karim Nagi, Nicolas Audet, Rory Sleno, Mohammad Amraei, Mireille Hogue, Gianfranco Balboni, Peter W. Schiller, Michel Bouvier, Terence E. Hébert and Graciela Pineyro
Molecular Pharmacology February 1, 2013, 83 (2) 416-428; DOI: https://doi.org/10.1124/mol.112.081950
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