Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells

Proc Natl Acad Sci U S A. 1992 May 1;89(9):3825-9. doi: 10.1073/pnas.89.9.3825.

Abstract

The psychoactive properties of Cannabis sativa and its major biologically active constituent, delta 9-tetrahydrocannabinol, have been known for years. The recent identification and cloning of a specific cannabinoid receptor suggest that cannabinoids mimic endogenous compounds affecting neural signals for mood, memory, movement, and pain. Using whole-cell voltage clamp and the cannabinomimetic aminoalkylindole WIN 55,212-2, we have found that cannabinoid receptor activation reduces the amplitude of voltage-gated calcium currents in the neuroblastoma-glioma cell line NG108-15. The inhibition is potent, being half-maximal at less than 10 nM, and reversible. The inactive enantiomer, WIN 55,212-3, does not reduce calcium currents even at 1 microM. Of the several types of calcium currents in NG108-15 cells, cannabinoids predominantly inhibit an omega-conotoxin-sensitive, high-voltage-activated calcium current. Inhibition was blocked by incubation with pertussis toxin but was not altered by prior treatment with hydrolysis-resistant cAMP analogues together with a phosphodiesterase inhibitor, suggesting that the transduction pathway between the cannabinoid receptor and calcium channel involves a pertussis toxin-sensitive GTP-binding protein and is independent of cAMP metabolism. However, the development of inhibition is considerably slower than a pharmacologically similar pathway used by an alpha 2-adrenergic receptor in these cells. Our results suggest that inhibition of N-type calcium channels, which could decrease excitability and neurotransmitter release, may underlie some of the psychoactive effects of cannabinoids.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzoxazines
  • Calcium Channels / drug effects*
  • Cannabinoids / pharmacology*
  • Electric Conductivity
  • Glioma
  • In Vitro Techniques
  • Ion Channel Gating / drug effects
  • Membrane Potentials
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Neuroblastoma
  • Norepinephrine / pharmacology
  • Pertussis Toxin
  • Rats
  • Receptors, Cannabinoid
  • Receptors, Drug / physiology*
  • Tumor Cells, Cultured
  • Virulence Factors, Bordetella / pharmacology

Substances

  • Benzoxazines
  • Calcium Channels
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Virulence Factors, Bordetella
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Pertussis Toxin
  • Norepinephrine