Paracrine Transactivation of the CB1 Cannabinoid Receptor by AT1 Angiotensin and Other Gq/11 Protein-coupled Receptors

Turu, Gábor; Várnai, Péter; Gyombolai, Pál; Szidonya, László; Offertáler, László; Bagdy, György; Kunos, George; Hunyady, László

doi:10.1074/jbc.m109.003681

Cited by 56 publications

(70 citation statements)

References 54 publications

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“…Namely, it was observed that inhibition of DAGL in these cells led to inhibition of the constitutive activity of CB 1 receptors, and similar results were obtained in HEK-293 cells (Turu et al, 2007(Turu et al, , 2009). The transactivation of cannabinoid CB1 receptors by Ang II is supported by the finding that showed an inhibitory effect of AM 251, inverse agonist of CB 1 receptors, on the hypertensive effect of Ang II injected directly into the hypothalamic paraventricular nucleus of anaesthetized rats (Gyombolai et al, 2012).…”

Section: Discussionsupporting

confidence: 69%

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Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Gyires

Rónai

Zádori

et al. 2014

Molecular and Cellular Endocrinology

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The aim of the present study was to analyze whether angiotensin II via the endocannabinoid system can induce gastric mucosal protection, since transactivation of cannabinoid CB1 receptors by angiotensin AT1 receptor in CHO cells was described. Experimental ulcer was induced by acidified ethanol given orally in male Wistar rats, CB1(+/+) wild type and CB1(-/-) knock out mice. The compounds were administered intracerebroventricularly. It was found, that 1./ Angiotensin II inhibited the ethanol-induced gastric lesions (11.9-191 pmol); the effect of angiotensin II (191 pmol) was inhibited by the CB1 receptor inverse agonist AM 251 (1.8 nmol) and the inhibitor of diacylglycerol lipase (DAGL), tetrahydrolipstatin (0.2 nmol). 2./ Angiotensin II exerted gastroprotection in wild type, but not in CB1(-/-) mice. 3./ The gastroprotective effect of angiotensin II (191 pmol) was reduced by atropine (1 mg/kg i.v.) and bilateral cervical vagotomy. In conclusion, stimulation of central angiotensin AT1 receptors via activation of cannabinoid CB1 receptors induces gastroprotection in a DAGL-dependent and vagus-mediated mechanism.

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Section: Discussionsupporting

confidence: 69%

“…Accordingly, inhibition of DAGL in CHO cells interfered with the activation of CB 1 receptors (Turu et al, 2007). The inhibitory effect of DAGL-inhibitor on these processes suggests that these actions are mediated mainly by 2-AG (Bisogno et al, 2005;Makara et al, 2005;Turu et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Gyires

Rónai

Zádori

et al. 2014

Molecular and Cellular Endocrinology

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“…When the G q -coupled AT 1 R was coexpressed with CB 1 R in CHO cells, AT 1 R stimulation with angiotensin II lead to a diacylglycerol lipase (DAGL)-mediated transactivation of CB 1 Rs (Turu et al 2007). This effect was mediated by the formation of endocannabinoids in CHO cells, and similar CB 1 R transactivation was observed with all other tested G qcoupled GPCRs (Turu et al 2009). Since G q/11 activation can lead to generation of 2-AG, the abovementioned interaction between orexin-1 receptor and CB 1 R may also occur with this mechanism.…”

Section: Modulation Of Ion Channelssupporting

confidence: 64%

Signal transduction of the CB1 cannabinoid receptor

Turu

Hunyady

2009

Journal of Molecular Endocrinology

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The CB 1 cannabinoid receptor (CB 1 R) is the major cannabinoid receptor in neuronal cells and the brain, but it also occurs in endocrine cells and other peripheral tissues. CB 1 R is a member of the superfamily of G-protein-coupled receptors (GPCRs), which are characterized by seven transmembrane helices. The major mediators of CB 1 R are the G proteins of the G i/o family, which inhibit adenylyl cyclases in most tissues and cells, and regulate ion channels, including calcium and potassium ion channels. Regulation of ion channels is an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to depolarization and Ca 2C -mobilizing hormones. However, evidence exists that CB 1 Rs can also stimulate adenylyl cyclase via G s , induce receptor-mediated Ca 2C fluxes and stimulate phospholipases in some experimental models. Stimulation of CB 1 R also leads to phosphorylation and activation of mitogen-activated protein kinases (MAPK), such as p42/p44 MAPK, p38 MAPK and c-Jun N-terminal kinase, which can regulate nuclear transcription factors. Activated and phosphorylated CB 1 Rs also associate with b-arrestin molecules, which can induce the formation of signalling complexes and participate in the regulation of GPCR signalling. Recent data also suggest that CB 1 Rs can form homo-and heterodimers/oligomers, and the altered pharmacological properties of these receptor complexes may explain the pharmacological differences observed in various tissues.

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“…The receptor plays role in many important physiological processes, such as learning, thinking, nociception or the regulation of food-intake (Pacher et al, 2006). Activation of presynaptic CB 1 Rs by postsynaptic endocannabinoid release, which mediates retrograde transmission, is a key regulatory mechanism in the central nervous system, but paracrine activation of CB 1 Rs with a similar mechanism can also occur in extraneural tissues (Freund et al, 2003;Gyombolai et al, 2012;Sanchez et al, 2001;Turu et al, 2009;Szekeres et al, 2012). The cellular signaling events following CB 1 R activation are mainly associated with the activation of heterotrimeric G i/o -proteins and include inhibition of adenylyl cyclases, activation of K ir channels, inhibition of Ca v channels and phosphorylation and activation of different subtypes of mitogen-activated protein kinases (MAP kinases) (Turu and Hunyady, 2010).…”

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confidence: 99%

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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CB 1 cannabinoid receptor (CB 1 R) undergoes both constitutive and agonist-induced internalization, but the underlying mechanisms of these processes and the role of β-arrestins in the regulation of CB 1 R function are not completely understood. In this study, we followed CB 1 R internalization using confocal microscopy and bioluminescence resonance energy transfer measurements in HeLa and Neuro-2a cells. We found that upon activation CB 1 R binds β-arrestin2 (β-arr2), but not β-arrestin1. Furthermore, both the expression of dominant-negative β-arr2 (β-arr2-V54D) and siRNA-mediated knock-down of β-arr2 impaired the agonist-induced internalization of CB 1 R. In contrast, neither β-arr2-V54D nor β-arr2-specific siRNA had a significant effect on the constitutive internalization of CB 1 R. However, both constitutive and agonist-induced internalization of CB 1 R were impaired by siRNA-mediated depletion of clathrin heavy chain. We conclude that although clathrin is required for both constitutive and agonist-stimulated internalization of CB 1 R, β-arr2 binding is only required for agonist-induced internalization of the receptor suggesting that the molecular mechanisms underlying constitutive and agonist-induced internalization of CB 1 R are different.

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Paracrine Transactivation of the CB1 Cannabinoid Receptor by AT1 Angiotensin and Other Gq/11 Protein-coupled Receptors

Cited by 56 publications

References 54 publications

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Signal transduction of the CB1 cannabinoid receptor

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

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