Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression.
Although the endocannabinoid anandamide is frequently described to act predominantly in the cardiovascular system, the molecular mechanisms of its signaling remained unclear. In human endothelial cells, two receptors for anandamide were found, which were characterized as cannabinoid 1 receptor (CB1R; CNR1) and G-protein-coupled receptor 55 (GPR55). Both receptors trigger distinct signaling pathways. It crucially depends on the activation status of integrins which signaling cascade becomes promoted upon anandamide stimulation. Under conditions of inactive integrins, anandamide initiates CB1R-derived signaling, including Gi-protein-mediated activation of spleen tyrosine kinase (Syk), resulting in NFkappaB translocation. Furthermore, Syk inhibits phosphoinositide 3-kinase (PI3K) that represents a key protein in the transduction of GPR55-originated signaling. However, once integrins are clustered, CB1R splits from integrins and, thus, Syk cannot further inhibit GPR55-triggered signaling resulting in intracellular Ca2+ mobilization from the endoplasmic reticulum (ER) via a PI3K-Bmx-phospholipase C (PLC) pathway and activation of nuclear factor of activated T-cells. Altogether, these data demonstrate that the physiological effects of anandamide on endothelial cells depend on the status of integrin clustering.
Waldeck-Weiermair
Markus
M
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, A8010, Austria.
Zoratti
Cristina
C
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, A8010, Austria.
Osibow
Karin
K
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, A8010, Austria.
Balenga
Nariman
N
Institute of Experimental and Clinical Pharmacology, Medical University Graz, Graz, A8010, Austria.
Goessnitzer
Edith
E
Institute of Pharmaceutical Chemistry, University Graz, Graz Austria.
Waldhoer
Maria
M
Institute of Experimental and Clinical Pharmacology, Medical University Graz, Graz, A8010, Austria.
Malli
Roland
R
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, A8010, Austria.
Graier
Wolfgang F
WF
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, A8010, Austria.
D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002460:Cell Line; D063388:Endocannabinoids; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D000097782:NF-kappaB-Inducing Kinase
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D053284:Polyunsaturated Alkamides; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D000072377:Syk Kinase; D000097782:NF-kappaB-Inducing Kinase; C524885:GPR55 protein, human; C000606896:SYK protein, human; C078814:anandamide