Ligand- and Heterodimer-Directed Signaling of the CB<sub>1</sub> Cannabinoid Receptor

Hudson, Brian D.; Hébert, Terence E.; Kelly, Melanie E. M.

doi:10.1124/mol.109.060251

Cited by 99 publications

(72 citation statements)

References 77 publications

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“…Ligands for CB 1 R, including the ECBs, synthetic cannabinoids such as WIN and phytocannabinoids such as Δ 9 -tetrahydrocannabinol, all bind different residues on the receptor. This has been suggested to give rise to ligand-specific conformational changes in CB 1 R leading to activation of different downstream signaling pathways Varga et al 2008;Hudson et al 2010). Moreover, the functional selectivity of a given ligand can be cell-type-specific (Bosier et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

et al. 2017

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Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB 1 receptor (CB 1 R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB 1 Rs in Schaffer-Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP. The second cascade is pregnenolone insensitive and LPP specific; it entails co-operative CB 1 R/β1-integrin signaling to effect synaptic potentiation via stable enhancement of transmitter release. The latter cascade is engaged during LPP-dependent learning. These results link atypical ECB signaling to the encoding of a fundamental component of episodic memory and suggest a novel route whereby endogenous and exogenous cannabinoids affect cognition.

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Section: Discussionmentioning

confidence: 99%

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

et al. 2017

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“…Thus, if spice use is suspected, liquid chromatography-tandem mass spectroscopy from a serum sample may help confirm JWH-018, AM-2201, JWH-019, JWH-073, JWH-250, and others. 7,8 Nevertheless, the formula of spice varies by supplier, and can include such toxic chemicals as linoleic acid, palmitic acid, oleamide, palmitoylethanolamide, eugenol, thymol, acetyl vanillin, benzyl benzoate, a-tocopherol, vitamin E, and b 2 -adrenergic agonists. 2 Although the 5 cannabinoids are schedule I drugs as of 2011, the manufacturing of the street drugs is not currently regulated; the manufacturers are often unknown because these products are purchased through internet vendors both wholesale and retail.…”

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confidence: 99%

Ischemic stroke after use of the synthetic marijuana “spice”

et al. 2013

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Objectives: To report and associate acute cerebral infarctions in 2 young, previously healthy siblings with use of the street drug known as "spice" (a synthetic marijuana product, also known as "K2"), which they independently smoked before experiencing acute embolic-appearing ischemic strokes.Methods: We present history, physical examination, laboratory data, cerebrovascular imaging, echocardiogram, ECG, and hospital course of these patients.Results: We found that in both siblings spice was obtained from the same source. The drug was found to contain the schedule I synthetic cannabinoid JWH-018. Full stroke workup was unrevealing of a stroke etiology; urine drug screen was positive for marijuana.Conclusions: We found that our 2 patients who smoked the street drug spice had a temporal association with symptoms of acute cerebral infarction. This association may be confounded by contaminants in the product consumed (i.e., marijuana or an unidentified toxin) or by an unknown genetic mechanism. The imaging of both patients suggests an embolic etiology, which is consistent with reports of serious adverse cardiac events with spice use, including tachyarrhythmias and myocardial infarctions. Spice, a schedule I synthetic marijuana (also known as "K2"), is a recreational street drug with many known adverse effects, including seizures and myocardial infarction. However, to our knowledge, cerebral infarction associated with synthetic marijuana use has yet to be reported in the medical literature. Spice is frequently abused by young adults with increasing popularity because of its euphoric effects and the ease with which it is obtained, which creates the perception of "a legal high." The US Drug Enforcement Agency (DEA), law enforcement, hospitals, and poison control centers have noted gradually increasing use of spice in the United States since 2009. In 2011, 5 synthetic cannabinoids used in spice were categorized as schedule I substances under the Controlled Substances Act: JWH-018; JWH-073; 497; and cannabicyclohexanol. 1 At the time of our patients' presentations, spice was available for sale over-the-counter at convenience stores, smoke shops, gas stations, and over the Internet, and labeled as "herbal blends," "air fresheners," or "incense," often with the warning "not for human consumption."2 Common side effects of spice include tachycardia, vomiting, agitation, confusion, and hallucinations; more serious adverse reactions (seizures, myocardial infarction) have recently appeared in the medical literature. 2-4Furthermore, a number of spice-associated deaths have been reported in national news media. To our knowledge, the medical literature has not yet reported ischemic stroke associated with synthetic marijuana. We present 2 young siblings who experienced acute ischemic strokes soon after smoking synthetic marijuana.CASE REPORTS Patient A. A 26-year-old man was brought to the emergency department by emergency medical services approximately 50 minutes after he had the sudden onset of dysarthria, expressive ...

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“…The coupling can vary in a temporary, tissue-or ligand-specific manner (13,14). Dissecting GPCR signaling on the basis of which pathways are activated will shed new light on the mechanism of hormonal action, which in turn will enable the development of novel strategies for the treatment of GPCR-related disorders, and more efficient and safer therapeutics that act in a signalpathway-specific manner.…”

Section: Introductionmentioning

confidence: 99%

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

Press

Zvagelsky

Vyazmensky

et al. 2016

Biophysical Journal

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The signaling of a G protein-coupled receptor (GPCR) is dictated by the complementary responsiveness of interacting intracellular effectors such as G proteins. Many GPCRs are known to couple to more than one G protein subtype and induce a multitude of signaling pathways, although the in vivo relevance of particular pathways is mostly unrecognized. Dissecting GPCR signaling in terms of the pathways that are activated will boost our understanding of the molecular fundamentals of hormone action. The structural determinants governing the selectivity of GPCR/G protein coupling, however, remain obscure. Here, we describe the design of soluble GPCR mimetics to study the details of the interplay between G-proteins and activators. We constructed functional mimetics of the intracellular domain of a model GPCR, the thyrotropin receptor. We based the construction on a unique scaffold, 6-Helix, an artificial protein that was derived from the elements of the trimer-of-hairpins structure of HIV gp41 and represents a bundle of six a-helices. The 6-Helix scaffold, which endowed the substituted thyrotropin receptor intracellular domain elements with spatial constraints analogous to those found in native receptors, enabled the reconstitution of a microdomain that consists of intracellular loops 2 and 3, and is capable of binding and activating Ga-(s). The 6-Helix-based mimetics could be used as a platform to study the molecular basis of GPCR/G protein recognition. Such knowledge could help investigators develop novel therapeutic strategies for GPCR-related disorders by targeting the GPCR/G protein interfaces and counteracting cellular dysfunctions via focused tuning of GPCR signaling.

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Ligand- and Heterodimer-Directed Signaling of the CB₁ Cannabinoid Receptor

Cited by 99 publications

References 77 publications

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Ischemic stroke after use of the synthetic marijuana “spice”

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

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Ligand- and Heterodimer-Directed Signaling of the CB1 Cannabinoid Receptor

Cited by 99 publications

References 77 publications

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Ischemic stroke after use of the synthetic marijuana “spice”

Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain

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Ligand- and Heterodimer-Directed Signaling of the CB₁ Cannabinoid Receptor