Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis.

Abstract

Serotonin (5-HT) stimulated the release of arachidonic acid in hippocampal neurons cocultured with glial cells but not in glial cultures alone. Similar results were observed for the 5-HT-stimulated release of inositol phosphates. These results suggest a neural but not glial orign of both responses.Pharmacological studies suggested that release of arachidonic acid and inositol phosphates was mediated by a type 2 5-HT (5-HT2) receptor. 5-HT-stimulated release of arachidonic acid was also detected in cortical neurons, which contain high levels of 5-HT2 receptors, but not striatum, spinal cord, or cerebellar granule cells, which have very low levels or are devoid of 5-HT2 receptors. The phorbol ester phorbol 12-myristate 13-acetate augmented the 5-HT-stimulated release of arachidonic acid but inhibited the 5-HT-stimulated release of inositol phosphates. 5-HT-stimulated release of arachidonic acid, but not inositol phosphates, was dependent on extracellular calcium. 5-HT stimulated the release of [3U1lysophosphatidylcholine from [3UHcholine-labeled cells with no increase in the release of [3HUcholine or phospho[3Ulcholine. These data suggest that 5-UT stimulated the release of arachidonic acid in hippocampal neurons through the activation of phospholipase A2, independent of the activation of phospholipase C.The excitable membranes of the central nervous system are enriched in 20-carbon unsaturated fatty acids, particularly arachidonic acid (1). Arachidonic acid serves as a precursor to a number of biologically active acid lipids, including prostaglandins, leukotrienes, and thromboxanes. Arachidonic acid and its eicosanoid metabolites are released after activation ofcertain neurotransmitter receptors and may play a role in neurotransmission. Recent studies have demonstrated (2-4) receptor-mediated release of eicosanoids in brain cells in primary culture. N-Methyl-D-aspartate stimulated the release of arachidonic acid, 11-HETE, and 12-HETE (where HETE is hydroxyeicosatetraenoic acid) in striatal cells (2) as well as arachidonic acid in cerebellar granule cells (3). Bradykinin stimulated arachidonic acid mobilization from dorsal root ganglion neurons (4). It is not clear from these studies whether the release of arachidonic acid is independent of inositolphospholipid turnover and whether the response is neural or glial in origin. Recent studies demonstrated a-adrenergic receptor stimulation caused arachidonic acid release from spinal cord, hippocampal, and cortical neurons, but not from glia cells, grown in primary culture that was independent of inositolphospholipid turnover (5).Central serotonin (5-HT) receptors are involved in sleep, depression, hallucinations, anxiety, sexual behavior, memory, appetite control, and thermoregulation (6). 5-HT receptors exist as several subtypes and transduce their signals by way of multiple intracellular messengers (7). Types 1A, 1B, and 1D 5-HT receptors (5-HT1A, 5-HT1B, and 5-HTlD) modulate adenylate cyclase activity and types 1C and 2 5-HT (5-HT1c and 5-HT2) receptors incr...

Angiotensin II-Induced Pulmonary Edema in a Rabbit Model

“…The stimulation of 5-HT2 receptor modulates the in crease of inositol phospholipid turnover and release of arachidonic acid (18,19), and these may also stimulate the release of intracellular calcium. The increase of cellular calcium ions is thought to be an important trig ger in ischemic cell death (20,21).…”

Imaging Brain Phospholipase A2 Activation in Awake Rats in Response to the 5-HT2A/2C Agonist (±)2,5-Dimethoxy-4-Iodophenyl-2-Aminopropane (DOI)

“…Recall that PLA 2 can be activated when a ligand binds to any of a number of receptor subtypes, including 5-HT 2 receptors (Axelrod, 1995;Cooper et al, 1996;Felder et al, 1990). 5-HT 2 receptors are widely distributed in rat brain (Appel et al, 1990;Morilak et al, 1993;Pazos and Palacios, 1985).…”

“…In brain, 5-HT 2 receptors can be coupled via G-proteins to phospholipase C (PLC) activation, generating inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol as second messengers (Conn and Sanders-Bush, 1986b;Edagawa et al, 2000), or to phospholipase A 2 (PLA 2 ) activation, releasing arachidonic acid (AA) from phospholipids (Axelrod, 1995;Berg et al, 1998;Felder et al, 1990;Tournois et al, 1998). Both AA and its eicosanoid metabolites are important second messengers (Shimizu and Wolfe, 1990).…”

“…Tracer incorporation in response to an appropriate agonist reflects PLA 2 -mediated hydrolysis of unlabeled AA from the stereospecifically numbered (sn)-2 position of synaptic brain phospholipids Fonlupt et al, 1994;Grange et al, 1998;Jones et al, 1996), independent of changes in regional cerebral blood flow (rCBF) (Chang et al, 1997;DeGeorge et al, 1991;Robinson et al, 1992;Robinson and Rapoport, 1986;Yamazaki et al, 1994). Receptors coupled to PLA 2 via membrane G-proteins include cholinergic muscarinic M 1 and M 3 receptors, dopaminergic D 2 receptors, and serotonergic 5-HT 2 receptors (Axelrod, 1995;Bayon et al, 1997;Cooper et al, 1996;DeGeorge et al, 1991;Felder et al, 1990;Hayakawa et al, 2001;Vial and Piomelli, 1995). PLA 2 can also be activated when Ca 2+ enters cells by glutamate acting at N-methyl-d-aspartate (NMDA) receptors or by acetylcholine acting at nicotinic receptors (Brooks et al, 1989;Cooper et al, 1996;Vijayaraghavan et al, 1995).…”

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).…”