Paracrine transactivation of the CB1 cannabinoid receptor by AT1 angiotensin and other Gq/11 protein-coupled receptors.
Intracellular signaling systems of G protein-coupled receptors are well established, but their role in paracrine regulation of adjacent cells is generally considered as a tissue-specific mechanism. We have shown previously that AT(1) receptor (AT(1)R) stimulation leads to diacylglycerol lipase-mediated transactivation of co-expressed CB(1)Rs in Chinese hamster ovary cells. In the present study we detected a paracrine effect of the endocannabinoid release from Chinese hamster ovary, COS7, and HEK293 cells during the stimulation of AT(1) angiotensin receptors by determining CB(1) cannabinoid receptor activity with bioluminescence resonance energy transfer-based sensors of G protein activation expressed in separate cells. The angiotensin II-induced, paracrine activation of CB(1) receptors was visualized by detecting translocation of green fluorescent protein-tagged beta-arrestin2. Mass spectrometry analyses have demonstrated angiotensin II-induced stimulation of 2-arachidonoylglycerol production, whereas no increase of anandamide levels was observed. Stimulation of G(q/11)-coupled M(1), M(3), M(5) muscarinic, V(1) vasopressin, alpha(1a) adrenergic, B(2) bradykinin receptors, but not G(i/o)-coupled M(2) and M(4) muscarinic receptors, also led to paracrine transactivation of CB(1) receptors. These data suggest that, in addition to their retrograde neurotransmitter role, endocannabinoids have much broader paracrine mediator functions during activation of G(q/11)-coupled receptors.
From the Department of Physiology, Faculty of Medicine, Budapest, Hungary.
Gábor
G
Turu
From the Department of Physiology, Faculty of Medicine, Budapest, Hungary.
Péter
P
Várnai
From the Department of Physiology, Faculty of Medicine, Budapest, Hungary.
Pál
P
Gyombolai
From the Department of Physiology, Faculty of Medicine, Budapest, Hungary.
László
L
Szidonya
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9413.
László
L
Offertaler
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; Group of Neuropsychopharmacology, Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary.
György
G
Bagdy
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9413.
George
G
Kunos
From the Department of Physiology, Faculty of Medicine, Budapest, Hungary; Laboratory of Neurobiochemistry and Molecular Physiology, Budapest, Hungary. Electronic address: Hunyady@eok.sote.hu.
László
L
Hunyady
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D031541:Fluorescence Resonance Energy Transfer; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019899:Paracrine Communication; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000071557:beta-Arrestins
D019390:Arrestins; D063385:Cannabinoid Receptor Modulators; D044140:Receptor, Angiotensin, Type 1; D043884:Receptor, Cannabinoid, CB1; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11