Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes
Abstract
Two cannabinoid receptors belonging to the superfamily of G protein-coupled membrane receptors have been identified and cloned: the neuronal cannabinoid receptor (CB1) and the peripheral cannabinoid receptor (CB2). They have been shown to couple directly to the G(i/o) subclass of G proteins and to mediate inhibition of adenylyl cyclase upon binding of a cannabinoid agonist. In several cases, however, cannabinoids have been reported to stimulate adenylyl cyclase activity, although the mechanism by which they did so was unclear. With the cloning of nine adenylyl cyclase isozymes with various properties, including different sensitivities to alpha(s), alpha(i/o), and betagamma subunits, it became important to assess the signaling pattern mediated by each cannabinoid receptor via the different adenylyl cyclase isozymes. In this work, we present the results of cotransfection experiments between the two types of cannabinoid receptors and the nine adenylyl cyclase isoforms. We found that independently of the method used to stimulate specific adenylyl cyclase isozymes (e.g., ionomycin, forskolin, constitutively active alpha(s), thyroid-stimulating hormone receptor activation), activation of the cannabinoid receptors CB1 and CB2 inhibited the activity of adenylyl cyclase types I, V, VI, and VIII, whereas types II, IV, and VII were stimulated by cannabinoid receptor activation. The inhibition of adenylyl cyclase type III by cannabinoids was observed only when forskolin was used as stimulant. The activity of adenylyl cyclase type IX was inhibited only marginally by cannabinoids.
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Stimulation of CB1R recruits various signaling pathways, including Gi/o coupling that reduces adenylyl cyclase and downregulates cAMP/PKA signaling, Gβγ-induced PLC-β-mediated calcium influx, and activation of MAP kinases.
“Stimulation of CB1R recruits various signaling pathways [22]. These pathways include CB1R coupling to Gi/o proteins that reduces adenylyl cyclase activity and downregulates cyclic AMP/protein kinase A signaling [23], by Gβγ-induced phospholipase C-β-mediated increases in intracellular calcium influx, and by activation of mitogen-activated protein kinases [24,25].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [24]
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- Authors
- Rhee, M., Bayewitch, M., Avidor‐Reiss, T., Levy, R., & Vogel, Z.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Vogel, Zvi
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1998-10
- Volume
- 71
- Issue
- 4
- Pages
- 1525-1534
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2035086154
- Cited by
- 159
- References
- 56
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 5 · 2017: 6 · 2016: 7 · 2015: 3 · 2014: 10 · 2013: 4 · 2012: 1
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da006265-09)
- National Institute on Drug Abuse (DA 06265)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cannabinoid receptors, CB1 receptor, CB2 receptor, G protein-coupled receptors, G protein signaling, adenylate cyclase inhibition, forskolin, beta gamma subunits, thyroid-stimulating hormone receptor, cotransfection
- MeSH terms
- Adenylyl Cyclase Inhibitors, Adenylyl Cyclases, Animals, Cannabinoids, Enzyme Activation, Humans, Isoenzymes, Morpholines, Naphthalenes, Receptors, Drug, Dronabinol, Transfection, COS Cells, Receptors, Cannabinoid, Receptor, Cannabinoid, CB2, Benzoxazines, Rats
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