Characterization of the endocannabinoid system, CB1 receptor signalling and desensitization in human myometrium

Brighton, Paul J.; Marczylo, Timothy H.; Rana, Shashi; Konje, Justin C.; Willets, Jonathon M.

doi:10.1111/j.1476-5381.2011.01425.x

Cited by 21 publications

(13 citation statements)

References 46 publications

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“…Confirmatory evidence supporting the hypothesis that anandamide can inhibit forskolin-stimulated cyclic AMP production by activating CB 1 receptors has come from experiments both with CB 1 -selective antagonists/inverse agonists and with untransfected cells. Thus, it has been found first that this effect of anandamide can be prevented by SR141716A (IC 50 ¼ 143 nM) in human CB 1 but not in human CB 2 -transfected cells (Felder et al 1995), and by AM251, at 1 μM, both in human neocortical synaptosomes (Steffens et al 2005) and in human myometrial smoothmuscle cells (Brighton et al 2011), and second that this effect of anandamide is undetectable in untransfected CHO cells (Bonhaus et al 1998;Felder et al 1993;Vogel et al 1993). SR141716A or AM251 (1 μM) has also been found to prevent inhibition of forskolin-stimulated cyclic AMP production induced in rat cortical neurons by 2-arachidonoylglycerol (Stella et al 1997), in mouse neuroblastoma NIE 115 cells by oleamide (Leggett et al 2004) and in human neocortical synaptosomes by noladin ether (Steffens et al 2005).…”

Section: Cyclic Amp Assaymentioning

confidence: 95%

Endocannabinoids and Their Pharmacological Actions

Pertwee

2015

Handbook of Experimental Pharmacology

245

235

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The endocannabinoid system consists of G protein-coupled cannabinoid CB(1) and CB(2) receptors, of endogenous compounds known as endocannabinoids that can target these receptors, of enzymes that catalyse endocannabinoid biosynthesis and metabolism, and of processes responsible for the cellular uptake of some endocannabinoids. This review presents in vitro evidence that most or all of the following 13 compounds are probably orthosteric endocannabinoids since they have all been detected in mammalian tissues in one or more investigation, and all been found to bind to cannabinoid receptors, probably to an orthosteric site: anandamide, 2-arachidonoylglycerol, noladin ether, dihomo-γ-linolenoylethanolamide, virodhamine, oleamide, docosahexaenoylethanolamide, eicosapentaenoylethanolamide, sphingosine, docosatetraenoylethanolamide, N-arachidonoyldopamine, N-oleoyldopamine and haemopressin. In addition, this review describes in vitro findings that suggest that the first eight of these compounds can activate CB(1) and sometimes also CB(2) receptors and that another two of these compounds are CB(1) receptor antagonists (sphingosine) or antagonists/inverse agonists (haemopressin). Evidence for the existence of at least three allosteric endocannabinoids is also presented. These endogenous compounds appear to target allosteric sites on cannabinoid receptors in vitro, either as negative allosteric modulators of the CB1 receptor (pepcan-12 and pregnenolone) or as positive allosteric modulators of this receptor (lipoxin A(4)) or of the CB(2) receptor (pepcan-12). Also discussed are current in vitro data that indicate the extent to which some established or putative orthosteric endocannabinoids seem to target non-cannabinoid receptors and ion channels, particularly at concentrations at which they have been found to interact with CB(1) or CB(2) receptors.

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Section: Cyclic Amp Assaymentioning

confidence: 95%

Endocannabinoids and Their Pharmacological Actions

Pertwee

2015

Handbook of Experimental Pharmacology

245

235

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“…Cellular signaling characterized in human myometrial smooth muscle ULTR cells (Brighton et al, 2009) and non-pregnant human myometrial cells in primary culture (Brighton, Marczylo, Rana, Konje, & Willets, 2011) indicated that stimulation of the CB 1 receptor by anandamide or methanandamide could promote an early phase ERK1/2 phosphorylation in response to the sequential activation of Gi/o, phosphatidylinositol-3-kinase (PI3K), and a Src kinase. In ULTR cells, the role of CB 1 receptors (but not CB 2 receptor or TRP channels) was established (Brighton et al, 2009).…”

Section: Cannabinoid Receptor Signaling Pathways Associated With Diffmentioning

confidence: 99%

CB 1 and CB 2 Receptor Pharmacology

Howlett

Abood

2017

Advances in Pharmacology

258

219

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The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of marijuana and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors is considered.

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“…smooth muscle (7), vas deferens (5), and myometrial smooth muscle (2)], where they signal variously via G␣ i -dependent inhibition of adenylyl cyclase and G␤␥-dependent inhibition of voltage-gated L-type Ca 2ϩ channels, and activation of various kinases [phosphatidylinositol 3-kinase (PI 3-kinase), extracellular signal-regulated kinase (ERK1/2), and Src kinase].…”

mentioning

confidence: 99%

Inhibitory signaling by CB₁ receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase

Mahavadi

Sriwai

Huang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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We examined whether CB 1 receptors in smooth muscle conform to the signaling pattern observed with other G i-coupled receptors that stimulate contraction via two G␤␥-dependent pathways (PLC-␤3 and phosphatidylinositol 3-kinase/integrin-linked kinase). Here we show that the anticipated G␤␥-dependent signaling was abrogated. Except for inhibition of adenylyl cyclase via G␣ i, signaling resulted from G␤␥-independent phosphorylation of CB 1 receptors by GRK5, recruitment of ␤-arrestin1/2, and activation of ERK1/2 and Src kinase. Neither uncoupling of CB1 receptors from Gi by pertussis toxin (PTx) or Gi minigene nor expression of a G␤␥-scavenging peptide had any effect on ERK1/2 activity. The latter was abolished in muscle cells expressing ␤-arrestin1/2 siRNA. CB 1 receptor internalization and both ERK1/2 and Src kinase activities were abolished in cells expressing kinase-deficient GRK5(K215R). Activation of ERK1/2 and Src kinase endowed CB 1 receptors with the ability to inhibit concurrent contractile activity. We identified a consensus sequence ( 102 KSPSKLSP 109 ) for phosphorylation of RGS4 by ERK1/2 and showed that expression of a RGS4 mutant lacking Ser 103 /Ser 108 blocked the ability of anandamide to inhibit acetylcholine-mediated phosphoinositide hydrolysis or enhance G␣q:RGS4 association and inactivation of G␣q. Activation of Src kinase by anandamide enhanced both myosin phosphatase RhoA-interacting protein (M-RIP):RhoA and M-RIP:MYPT1 association and inhibited Rho kinase activity, leading to increase of myosin light chain (MLC) phosphatase activity and inhibition of sustained muscle contraction. Thus, unlike other Gi-coupled receptors in smooth muscle, CB1 receptors did not engage G␤␥ but signaled via GRK5/ ␤-arrestin activation of ERK1/2 and Src kinase: ERK1/2 accelerated inactivation of G␣q by RGS4, and Src kinase enhanced MLC phosphatase activity, leading to inhibition of ACh-stimulated contraction. beta arrestin; CB1 receptors; ERK1/2; GRK5; Src kinase THE PROPERTIES AND ROLE OF G protein-coupled cannabinoid receptors, CB 1 and CB 2 , have been extensively studied in their primary locations: the central and peripheral nervous system and the immune system, respectively (3,8,22,32). The location of CB 1 receptors in the brain (cerebral cortex, hippocampus, basal ganglia, amygdala, and cerebellum) correlates with the observed psychotropic effects of cannabinoids. It is increasingly evident, however, that CB 1 receptors and the endocannabinoid system that provides them with lipid ligands on demand are more widely distributed, though less abundantly than in neural tissue. Thus CB 1 receptors are expressed in both vascular and visceral smooth muscle [e.g., cerebral arterial smooth muscle (7), vas deferens (5), and myometrial smooth muscle (2)], where they signal variously via G␣ i -dependent inhibition of adenylyl cyclase and G␤␥-dependent inhibition of voltage-gated L-type Ca 2ϩ channels, and activation of various kinases [phosphatidylinositol 3-kinase (PI 3-kinase), extracellular signal-regulated kinase (E...

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Characterization of the endocannabinoid system, CB1 receptor signalling and desensitization in human myometrium

Cited by 21 publications

References 46 publications

Endocannabinoids and Their Pharmacological Actions

Endocannabinoids and Their Pharmacological Actions

CB 1 and CB 2 Receptor Pharmacology

Inhibitory signaling by CB₁ receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase

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Characterization of the endocannabinoid system, CB1 receptor signalling and desensitization in human myometrium

Cited by 21 publications

References 46 publications

Endocannabinoids and Their Pharmacological Actions

Endocannabinoids and Their Pharmacological Actions

CB 1 and CB 2 Receptor Pharmacology

Inhibitory signaling by CB1 receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase

Contact Info

Product

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About

Inhibitory signaling by CB₁ receptors in smooth muscle mediated by GRK5/β-arrestin activation of ERK1/2 and Src kinase