Dopamine D2 receptor signaling via the arachidonic acid cascade: modulation by cAMP-dependent protein kinase A and prostaglandin E2.
Recent studies have shown that, in Chinese hamster ovary cells transfected with D2-receptor cDNA, CHO(D2) cells, D2 agonists are potent in enhancing the release of [3H]arachidonic acid (AA) induced by stimulation of constitutive purinergic receptors or by application of Ca2+ ionophores. This facilitatory action is further amplified by the concomitant activation of D1 receptors, which per se have no effect on evoked [3H]AA release. Here, we review a series of experiments aimed at examining the molecular mechanism of this synergistic interaction. The results show that, in CHO(D2) cells: (a) application of 8-Br-cAMP or stimulation of constitutive prostaglandin (PG)E2 receptors augment the AA response produced by D2 agonists; (b) in CHO(D2) cells transfected with human beta 2-receptor cDNA, the beta-agonist, isoproterenol, produces a similar effect; (c) the potentiation of [3H]AA release produced by PGE2 and 8-Br-cAMP is prevented by overexpressing either a protein inhibitor of cAMP-dependent protein kinase (PKA) or a mutated form of pKA regulatory subunit incapable of binding cAMP; (d) mock-synergism is obtained in CHO(D2) cells overexpressing the catalytic subunit of PKA; (e) PGE2 is a major AA metabolite in stimulated CHO(D2) cells and its formation may contribute to the effect of D2 agonists on AA release. The results indicate that cAMP-induced activation of PKA represents a likely molecular basis for D1/D2 receptor synergism on AA release. They also suggest that additional membrane receptors, colocalized with D2 and positively linked to adenylyl cyclase, may exert a similar action. Furthermore, stimulation of PGE2 receptors by endogenously produced prostaglandin may participate in AA signaling at the D2 receptor, by providing a paracrine positive feedback loop.
Unité de Neurobiologie et Pharmacologie de l'INSERM, Paris, France.
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Piomelli
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Di Marzo
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D016466:CHO Cells / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016718:Arachidonic Acid; D000242:Cyclic AMP; D011494:Protein Kinases; D015232:Dinoprostone