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

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  • Author(s): Berecki G;Berecki G; Motin L; Motin L; Adams DJ; Adams DJ
  • Source:
    Molecular pharmacology [Mol Pharmacol] 2016 Jan; Vol. 89 (1), pp. 187-96. Date of Electronic Publication: 2015 Oct 21.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
    • Subject Terms:
      Calcium Channel Blockers/*pharmacology ; Calcium Channels, R-Type/*physiology ; GTP-Binding Protein beta Subunits/*physiology ; GTP-Binding Protein gamma Subunits/*physiology ; Receptors, Opioid, delta/*physiology ; Receptors, Opioid, kappa/*physiology ; Receptors, Opioid, mu/*physiology; Analgesics, Opioid/pharmacology ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology ; HEK293 Cells ; Humans ; Protein Subunits/physiology ; Receptors, Opioid, delta/agonists ; Receptors, Opioid, kappa/agonists ; Receptors, Opioid, mu/agonists
    • 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 Ba(2+) 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.
      (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
    • Accession Number:
      0 (Analgesics, Opioid)
      0 (Calcium Channel Blockers)
      0 (Calcium Channels, R-Type)
      0 (GTP-Binding Protein beta Subunits)
      0 (GTP-Binding Protein gamma Subunits)
      0 (Protein Subunits)
      0 (Receptors, Opioid, delta)
      0 (Receptors, Opioid, kappa)
      0 (Receptors, Opioid, mu)
      100929-53-1 (Enkephalin, Ala(2)-MePhe(4)-Gly(5)-)
    • Publication Date:
      Date Created: 20151023 Date Completed: 20160314 Latest Revision: 20151216
    • Publication Date:
      20240829
    • Accession Number:
      10.1124/mol.115.101154
    • Accession Number:
      26490245