G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors

Franklin, Jade M.; Carrasco, Gonzalo

doi:10.1074/jbc.m113.454843

Cited by 28 publications

(17 citation statements)

References 60 publications

(112 reference statements)

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“…Taken together these data suggest that changes in GRK5 are associated with the pathophysiology of severe neuropsychiatric illnesses associated with cognitive impairment. GRK5 abnormalities are also associated with cocaine administration, major depressive disorder, as well as behavioral hypersensitivity, consistent with the central role(s) of this molecule for linking GPCR activation with intracellular signaling processes (Bychkov et al, 2011a; Erdtmann-Vourliotis et al, 2001; Franklin and Carrasco, 2013; Gainetdinov et al, 1999; Ji et al, 2013; Kara et al, 2006; Luo et al, 2008; Ren et al, 2005; Shenoy et al, 2006; Zheng et al, 2012; Zhu et al, 2004; Zhu et al, 2013). …”

Section: 1 Discussionmentioning

confidence: 63%

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Funk

Haroutunian

Meador‐Woodruff

et al. 2014

Schizophrenia Research

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Background Current pharmacological treatments for schizophrenia target G protein-coupled receptors (GPCRs), including dopamine receptors. Ligand bound GPCRs are regulated by a family of G protein-coupled receptor kinases (GRKs), members of which uncouple the receptor from heterotrimeric G proteins, desensitize the receptor, and induce receptor internalization via the arrestin family of scaffolding and signaling molecules. GRKs initiate the activation of downstream signaling pathways, can regulate receptors and signaling molecules independent of GPCR phosphorylation, and modulate epigenetic regulators like histone deacetylases (HDACs). We hypothesize that expression of GRK proteins are altered in schizophrenia, consistent with previous findings of alterations up and downstream from this family of molecules that facilitate intracellular signaling processes. Methods In this study we measured protein expression via Western blot analysis for GRKs 2, 3, 5, and 6 in the anterior cingulate cortex of patients with schizophrenia (N = 36) and a comparison group (N = 33). To control for antipsychotic treatment we measured these same targets in haloperidol treated vs. untreated rats (N = 10 for both). Results We found increased levels of GRK5 in schizophrenia. No changes were detected in GRK protein expression in rats treated with haloperidol decanoate for 9 months. Conclusion These data suggest that increased GRK5 expression may contribute the the pathophysiology of schizophrenia via abnormal regulation of the cytoskeleton, endocytosis, signaling, GPCRs, and histone modification.

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Section: 1 Discussionmentioning

confidence: 63%

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Funk

Haroutunian

Meador‐Woodruff

et al. 2014

Schizophrenia Research

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“…Although CB 2 cannabinoid receptors are expressed in relatively low levels in the CNS [172] and are not directly associated with psychoactive effects produced by SCBs [173], prolonged activation of CB 2 cannabinoid receptors has been shown to upregulate 5-HT 2A serotonin receptors in mouse prefrontal cortex [174, 175]. 5-HT 2A serotonin receptors are the primary site of action for hallucinogenic drugs [176] and 5-HT 2A serotonin receptor dysfunction has been associated with mental disorders including anxiety [177] and psychosis [178].…”

Section: Scb Toxicity - Cb1 Versus Non-cb1 Cannabinoid Receptor Targetsmentioning

confidence: 99%

Synthetic Pot: Not Your Grandfather’s Marijuana

Ford

Tai

Fantegrossi

et al. 2017

Trends in Pharmacological Sciences

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In the early 2000’s in Europe and shortly thereafter in the USA, it was reported that “legal” forms of marijuana were being sold under the name K2 and/or Spice. Active ingredients in K2/Spice products were determined to be synthetic cannabinoids (SCBs), producing psychotropic actions via CB1 cannabinoid receptors, similar to those of Δ9-THC, the primary active constituent in marijuana. Often abused by adolescents and military personnel to elude detection in drug tests due to their lack of structural similarity to Δ9-THC, SCBs are falsely marketed as safe marijuana substitutes. Instead, SCBs are a highly structural diverse group of compounds, easily synthesized, which produce very dangerous adverse effects occurring by, as of yet, unknown mechanisms. Therefore, available evidence indicates that K2/Spice products are clearly not safe marijuana alternatives.

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“…For instance, chronic activation of CB2Rs has been shown to produce an upregulation of 5-HT 2A receptors in the prefrontal cortex of mice [66, 67]. CNS abnormalities in 5-HT 2A function can lead to mental disorders, including anxiety [68] and psychosis [69].…”

Section: Synthetic Cannabinoid Cellular Signalingmentioning

confidence: 99%

Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites

Tai

Fantegrossi

2016

Neuropharmacology of New Psychoactive Substances (NPS)

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Commercial preparations containing synthetic cannabinoids (SCBs) are rapidly emerging as drugs of abuse. Although often assumed to be “safe” and “legal” alternatives to cannabis, reports indicate that SCBs induce toxicity not often associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This chapter will summarize the evidence that use of SCBs poses greater health risks relative to marijuana and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to this increased toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs act as full CB1 and CB2 receptor agonists both in cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for and exhibit a range of intrinsic activities at CB1 and CB2 receptors. Finally, the potential for SCBs to cause adverse drug–drug interactions with other drugs of abuse, as well as with common therapeutic agents, will be discussed. Collectively, the evidence provided in this chapter indicates that SCBs should not be considered safe and legal alternatives to marijuana. Instead, the enhanced toxicity of SCBs relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2 receptors, highlights the inherent danger that may accompany use of these substances.

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G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors

Cited by 28 publications

References 60 publications

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Synthetic Pot: Not Your Grandfather’s Marijuana

Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites

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