The Search for Selective Ligands for the CB2 Receptor

Jw, Huffman

doi:10.2174/1381612003399347

Cited by 67 publications

(43 citation statements)

References 16 publications

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“…1B). The aminoalkylindole JWH015 is considered an efficacious, specific CB 2 agonist (8). Surprisingly, JWH015 also stimulates GPR55, with 3 M giving an average calcium rise of 100 nM in hGPR55-HEK293 cells (n ϭ 6, Fig.…”

Section: Activation Of Gpr55 By Cannabinoids Increases Intracellular mentioning

confidence: 98%

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

Lauckner

Jensen²,

Chen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

621

664

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The CB1 cannabinoid receptor mediates many of the psychoactive effects of ⌬ 9 THC, the principal active component of cannabis. However, ample evidence suggests that additional non-CB 1/CB2 receptors may contribute to the behavioral, vascular, and immunological actions of ⌬ 9 THC and endogenous cannabinoids. Here, we provide further evidence that GPR55, a G protein-coupled receptor, is a cannabinoid receptor. GPR55 is highly expressed in large dorsal root ganglion neurons and, upon activation by various cannabinoids (⌬ 9 THC, the anandamide analog methanandamide, and JWH015) increases intracellular calcium in these neurons. Examination of its signaling pathway in HEK293 cells transiently expressing GPR55 found the calcium increase to involve G q, G12, RhoA, actin, phospholipase C, and calcium release from IP 3R-gated stores. GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB 1 and CB2.orphan ͉ pain ͉ CB3 ͉ G protein-coupled receptor C annabis has been used and abused for its therapeutic and psychoactive properties for millennia. The effects of cannabinoid compounds are largely mediated by cannabinoid receptors. CB 1 , cloned in 1990 (1), is widely and highly expressed in the CNS, where it likely mediates the majority of the psychotropic and behavioral effects of cannabinoids. CB 2 is primarily expressed in peripheral tissues (2). Both CB 1 and CB 2 are 7-transmembrane G protein-coupled receptors that engage predominantly the G i/o family of G proteins. However, ample evidence suggests that additional receptors may contribute to the behavioral, vascular, and immunological actions of ⌬ 9 tetrahydrocannabinol (THC) and endogenous cannabinoids (3).It has been suggested that GPR55 is a novel cannabinoid receptor (reviewed in ref. 4). GPR55 is only 13.5% identical to CB 1 and 14.4% identical to CB 2 , and its mRNA is present in the brain and periphery (5-7). A recent study found that a variety of cannabinoid compounds stimulated GTP␥S binding in cells stably expressing GPR55 (6). Here, we report GPR55 activation by THC, JWH015, and anandamide increases intracellular calcium by activating signaling pathways quite distinct from those used by CB 1 and CB 2 . Results Activation of GPR55 by Cannabinoids Increases Intracellular Calcium.We first examined the signaling pathways activated by GPR55 in HEK293 cells transiently expressing human GPR55 (hGPR55). Perfusion with 5 M THC evoked a calcium increase (⌬[Ca 2ϩ ] i ) averaging Ϸ100 nM (n ϭ 7, Fig. 1 A and B). Perfusion with 3 M THC evoked a more modest increase (n ϭ 5, 50 nM; Fig. 1B). The agonist-induced calcium response was present in all cells tested, but because it varied in magnitude and time course, concurrent controls were always conducted. GPR55 was essential for the THC-evoked calcium rise because there was minimal calcium rise in nontransfected HEK293 cells exposed to 5 M THC (n ϭ 6, Fig. 1 A and B). A similar calcium increase was seen in CHO cells stably expressing hGPR55 (data not show...

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Section: Activation Of Gpr55 By Cannabinoids Increases Intracellular mentioning

confidence: 98%

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

Lauckner

Jensen²,

Chen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

621

664

View full text Add to dashboard Cite

show abstract

“…Other signaling pathways include coupling to ion channels (N-and P/Qtype Ca 2+ channels and voltage-gated K + channels), activation of phospholipase-C beta (PLCβ) and ceramide biosynthesis (Galve-Roperh et al 2013;Maccarrone et al 2014). THC and CBN bind to both CB 1 and CB 2 with high affinity, with the latter being more avid for CB 2 (Huffman 2000;Mahadevan et al 2000). Instead CBD, a non-psychoactive component, shows little affinity for both receptors (Mechoulam et al 2007).…”

Section: Target Receptors and Signaling Pathwaysmentioning

confidence: 99%

Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses

Chiurchiù

Leuti

Maccarrone

2015

J Neuroimmune Pharmacol

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The concept of the central nervous system (CNS) as an immune-privileged site, essentially due to the presence of the blood brain barrier, appears to be overly simplistic. Indeed, within healthy CNS immune activities are permitted and are required for neuronal function and host defense, not only due to the presence of the resident innate immune cells of the brain, but also by virtue of a complex cross-talk of the CNS with peripheral immune cells. Nonetheless, long-standing and persisting neuroinflammatory responses are most often detrimental and characterize several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors. In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders.

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“…In a second set of experiments, we investigated the mechanical antiallodynic, thermal antihyperalgesic, and thermal antiallodynic effects of the subplantar administration of different doses of the specific DOPr agonist DPDPE (38.7-232.3 nmol; Clark et al, 1986), the specific CB2R agonist JWH-015 (15.3-91.6 nmol;Huffman, 2000), or their corresponding vehicle in the ipsilateral and contralateral paws of sciatic nerve-injured WT mice at 21 days after surgery.…”

Section: Gene Expression Studiesmentioning

confidence: 99%

The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice

Hervera¹,

Negrete²,

Leánez³

et al. 2010

J Pharmacol Exp Ther

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Both ␦-opioid receptor (DOPr) and cannabinoid-2 receptor (CB2R) agonists attenuate neuropathic pain, but the precise mechanism implicated in these effects is not completely elucidated. We investigated whether nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric-oxide synthases could modulate DOPr and/or CB2R antiallodynic and antihyperalgesic effects through the peripheral nitric oxide-cGMP-protein kinase G (PKG) pathway activation and affect their expression during neuropathic pain. , and NOS2-KO mice, also was assessed. The subplantar administration of NANT, L-NIL, ODQ, or Rp-8-pCPTcGMPs dose-dependently inhibited neuropathic pain and enhanced the local effects of DPDPE or JWH-015. Moreover, although the basal levels of DOPr and CB2R mRNA were similar between WT and NOS-KO animals, nerve injury only decreased (DOPr) or increased (CB2R) their expression in the dorsal root ganglia of WT and NOS2-KO mice, and not in NOS1-KO mice. Results suggest that inactivation of the nitric oxide-cGMP-PKG peripheral pathway triggered by NOS1 and NOS2 enhanced the peripheral actions of DOPr and CB2R agonists and that nitric oxide synthesized by NOS1 is implicated in the peripheral regulation of DOPr and CB2R gene transcription during neuropathic pain.

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The Search for Selective Ligands for the CB2 Receptor

Cited by 67 publications

References 16 publications

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current

Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses

The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice

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