Dopamine D₂ Receptors Potentiate Arachidonate Release via Activation of Cytosolic, Arachidonate‐Specific Phospholipase A₂

Abstract

Several Gi‐linked neurotransmitter receptors, including dopamine D2 receptors, act synergistically with Ca2+‐mobilizing stimuli to potentiate release of arachidonic acid (AA) from membrane phospholipids. In brain, AA and its metabolites are thought to act as intracellular second messengers, suggesting that receptor‐dependent potentiation of AA release may participate in neuronal transmembrane signaling. To study the molecular mechanisms underlying this modulatory response, we have now used Chinese hamster ovary cells transfected with rat D2‐receptor cDNA, CHO(D2). Two antisense oligodeoxynucleotides corresponding to distinct cDNA sequences of cytosolic, AA‐specific phospholipase A2 (cPLA2) were synthesized and added to cultures of CHO(D2) cells. Incubation with antisense oligodeoxynucleotides inhibited D2 receptor‐dependent release of AA but had no effect on D2‐receptor binding or D2 inhibition of cyclic AMP accumulation. In addition, pharmacological experiments showed that D2 receptor‐dependent AA release was prevented by nonselective phospholipase inhibitors (such as mepacrine) but not by inhibitors of membrane‐bound, non‐AA‐specific PLA2 (such as p‐bromophenacyl bromide). cPLA2 is expressed in brain tissue. The results, showing that cPLA2 participates in receptor‐dependent potentiation of AA release in CHO(D2) cells, suggest that this phospholipase may serve a similar signaling function in brain.

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

“…In this regard, chronic lithium increased the level of DARPP-32 in the rat frontal cortex (Guitart and Nestler, 1992), which may explain its ability to activate the ERK-signaling cascade (Einat et al, 2003). In view of the interplay between D 2 -like receptors and NMDARs, it is not surprising that chronic LiCl suppresses increments in k* for AA in unanesthetized rats given quinpirole (Basselin et al, 2005a), an agonist of D 2 -like receptors coupled to PLA 2 via a G-protein (Bhattacharjee et al, 2005;Hayakawa et al, 2001;Huo and Healy, 1991;Vial and Piomelli, 1995). This suppression agrees with evidence that drugs that interfere with dopaminergic neurotransmission can be effective in BD (Bunney and Garland-Bunney, 1987;Bymaster and Felder, 2002;Fisher et al, 1991;Peet and Peters, 1995;Post et al, 1980;Sultzer and Cummings, 1989).…”

“…However, no method exists, as far as we know, to image the Ca 2 + signal or its downstream effects in the brain in vivo. In this paper, we present such a method, which extends our published method of imaging brain PLA 2 activation in unanesthetized rats given drugs that act at receptors coupled a G-protein to PLA 2 (Basselin et al, 2005a(Basselin et al, , b, 2003Bhattacharjee et al, 2005;DeGeorge et al, 1991;Qu et al, 2003)Fcholinergic muscarinic M 1,3,5 , dopaminergic D 2 -like and serotonergic 5-HT 2A/2C receptors (Axelrod, 1995;Bayon et al, 1997;Felder et al, 1990;Vial and Piomelli, 1995).…”

D-Amphetamine Stimulates D2Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

“…Dopaminergic, serotonergic and noradrenergic receptors can be coupled by G-proteins to different effector enzymes, including phospholipase A 2 (PLA 2 ). Phospholipase A 2 activation releases arachidonic acid (AA,) from membrane phospholipids (Axelrod, 1990;Garcia and Kim, 1997;Nilsson et al, 1998;Pavoine et al, 2003;Vial and Piomelli, 1995). Arachidonic acid and its eicosanoid products are important second messengers that can influence membrane excitability, regional cerebral blood flow (rCBF), gene transcription, mood, and sleep (Chen and Bazan, 2005;Fitzpatrick and Soberman, 2001;Niwa et al, 2000;Rapoport and Bosetti, 2002;Shimizu and Wolfe, 1990;Wang et al, 2005).…”

“…Importantly, k* is independent of changes in rCBF, thus reflecting only brain metabolic events (Chang et al, 1997;DeGeorge et al, 1991;Robinson et al, 1992;Robinson and Rapoport, 1986). Dopaminergic D 2 -like receptors can be coupled specifically to Ca 2 + -dependent AA-selective cytosolic PLA 2 (cPLA 2 ) (Clark et al, 1991;Dennis, 1994;Nilsson et al, 1998;Vial and Piomelli, 1995), which is localized on excitatory post-synaptic neuronal membranes and dendrites (Ong et al, 1999;Pardue et al, 2003). D 1 -like receptors have not been reported to be coupled to PLA 2 in normal brain (Bhattacharjee et al, 2005b), but rather to phospholipase C or adenylate cyclase (Cooper et al, 2003).…”

Chronic Lithium Administration to Rats Selectively Modifies 5-HT2A/2C Receptor-Mediated Brain Signaling Via Arachidonic Acid

“…Receptors that are coupled to PLA 2 via Gproteins include muscarinic M 1,3,5 receptors, dopaminergic D 2 receptors, and 5-HT 2A/2C receptors (Axelrod, 1995;Bayon et al, 1997;Felder et al, 1990;Vial and Piomelli, 1995), whereas NMDA receptors are coupled by allowing Ca 2 þ into the cell (Lazarewicz et al, 1990;Weichel et al, 1999). The released AA and its bioactive eicosanoid metabolites can influence many physiological processes, including membrane excitability, gene transcription, apoptosis, sleep, and behavior (Fitzpatrick and Soberman, 2001;Shimizu and Wolfe, 1990).…”