Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons
Abstract
Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predominately located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent (K(1/2) = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (omega-conotoxin-GVIA-sensitive) and P/Q-type (omega-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.
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CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels and positively regulates inwardly rectifying K+ channels, as well as calcineurin, to change the phosphorylation state of effector molecules.
“In addition, CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels [26] and positively regulates inwardly rectifying K+ channels [26,27], as well as protein serine/threonine phosphatase 2B (calcineurin, PP2B) to change the phosphorylation state of various effector molecules [28,29].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [27]
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- Authors
- Twitchell, W., Brown, S., & Mackie, K.
- Affiliations
- Department of Anesthesiology and
- University of Washington (US)
- ORCID
- Venue
- Journal of Neurophysiology
- Publisher
- American Physiological Society
- Published
- 1997-07-01
- Volume
- 78
- Issue
- 1
- Pages
- 43-50
- ISSN
- 0022-3077 (ISSN-L)
- 1522-1598
- OpenAlex
- W1949541784
- Cited by
- 544
- References
- 42
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 13 · 2022: 7 · 2021: 14 · 2020: 17 · 2019: 12 · 2018: 11 · 2017: 18 · 2016: 16 · 2015: 13 · 2014: 18 · 2013: 21 · 2012: 17
- FWCI
- 18.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurophysiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29da008934-05, 2t32da007278-31)
- National Institute on Drug Abuse (DA-08934, DA-07278)
- National Institute of Neurological Disorders and Stroke (NS 08174)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cannabinoids, CB1 receptor, N-type calcium channels, P/Q-type calcium channels, hippocampal neurons, WIN 55,212-2, anandamide, CP55,940, SR141716, omega-conotoxin GVIA, omega-conotoxin MVIIC, presynaptic modulation, synaptic transmission
- MeSH terms
- Animals, Arachidonic Acids, Calcium Channel Blockers, Cannabinoids, Cells, Cultured, Cyclohexanols, Hippocampus, Membrane Potentials, Morpholines, Naphthalenes, Neurons, Picrotoxin, Benzoxazines, Rats, Polyunsaturated Alkamides, Endocannabinoids
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