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Molecular Pharmacology

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Research ArticleArticle

Voltage-Gated R-Type Calcium Channel Inhibition via Human μ-, δ-, and κ-opioid Receptors Is Voltage-Independently Mediated by Gβγ Protein Subunits

Géza Berecki, Leonid Motin and David J. Adams
Molecular Pharmacology January 2016, 89 (1) 187-196; DOI: https://doi.org/10.1124/mol.115.101154
Géza Berecki
Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia
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Leonid Motin
Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia
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David J. Adams
Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia
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Abstract

Elucidating the mechanisms that modulate calcium channels via opioid receptor activation is fundamental to our understanding of both pain perception and how opioids modulate pain. Neuronal voltage-gated N-type calcium channels (Cav2.2) are inhibited by activation of G protein–coupled opioid receptors (ORs). However, inhibition of R-type (Cav2.3) channels by μ- or κ-ORs is poorly defined and has not been reported for δ-ORs. To investigate such interactions, we coexpressed human μ-, δ-, or κ-ORs with human Cav2.3 or Cav2.2 in human embryonic kidney 293 cells and measured depolarization-activated Ba2+ currents (IBa). Selective agonists of μ-, δ-, and κ-ORs inhibited IBa through Cav2.3 channels by 35%. Cav2.2 channels were inhibited to a similar extent by κ-ORs, but more potently (60%) via μ- and δ-ORs. Antagonists of δ- and κ-ORs potentiated IBa amplitude mediated by Cav2.3 and Cav2.2 channels. Consistent with G protein βγ (Gβγ) interaction, modulation of Cav2.2 was primarily voltage-dependent and transiently relieved by depolarizing prepulses. In contrast, Cav2.3 modulation was voltage-independent and unaffected by depolarizing prepulses. However, Cav2.3 inhibition was sensitive to pertussis toxin and to intracellular application of guanosine 5′-[β-thio]diphosphate trilithium salt and guanosine 5′-[γ-thio]triphosphate tetralithium salt. Coexpression of Gβγ-specific scavengers—namely, the carboxyl terminus of the G protein–coupled receptor kinase 2 or membrane-targeted myristoylated-phosducin—attenuated or abolished Cav2.3 modulation. Our study reveals the diversity of OR-mediated signaling at Cav2 channels and identifies neuronal Cav2.3 channels as potential targets for opioid analgesics. Their novel modulation is dependent on pre-existing OR activity and mediated by membrane-delimited Gβγ subunits in a voltage-independent manner.

Footnotes

    • Received July 30, 2015.
    • Accepted October 19, 2015.
  • ↵1 Current affiliation: Illawarra Health & Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522 Australia. Email: djadams{at}uow.edu.au

  • This work was supported by a National Health and Medical Research Council project grant [Grant 1034642] and an Australian Research Council Discovery Project grant [Grant DP1093115]. D.J.A. is an Australian Research Council Australian Professorial Fellow.

  • dx.doi.org/10.1124/mol.115.101154.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (1)
Molecular Pharmacology
Vol. 89, Issue 1
1 Jan 2016
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Research ArticleArticle

Cav2.3 Channel Inhibition via Opioid Receptor Activation

Géza Berecki, Leonid Motin and David J. Adams
Molecular Pharmacology January 1, 2016, 89 (1) 187-196; DOI: https://doi.org/10.1124/mol.115.101154

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Research ArticleArticle

Cav2.3 Channel Inhibition via Opioid Receptor Activation

Géza Berecki, Leonid Motin and David J. Adams
Molecular Pharmacology January 1, 2016, 89 (1) 187-196; DOI: https://doi.org/10.1124/mol.115.101154
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