Negative regulation of cytosolic phospholipase A(2) by melatonin in the rat pineal gland

In this paper evidence that supports a new role for melatonin as a negative endogenous regulator of cytosolic phospholipase A(2) (cPLA(2)) is presente d. When rat pineal glands were incubated in culture, time-dependent release of arachidonic acid (AA) was observed, which was significantly inhibited b y a known 85-kDa cPLA(2) inhibitor, methyl arachidonyl fluorophosphonate. C o-incubation with melatonin inhibited the AA release in a concentration-dep endent manner, and this decrease was accompanied by a reduction of cPLA(2) protein and mRNA expression. Melatonin-receptor agonists, 2-iodo-N-butanoyl -5-methoxytryptamine and 5-methoxycarbonylamino-N-acetyltryptamine also dec reased AA release and cPLA(2) protein and mRNA levels, while pre-incubation with the melatonin receptor antagonists luzindole and 2-phenylmelatonin ab olished the melatonin effect. In vivo, as melatonin production reflected a typical diurnal variation, endogenous non-esterified AA and cPLA(2) mRNA le vels in the rat pineal gland showed an off-phase diurnal pattern in relatio n to melatonin levels. Intravenous administration of isoproterenol, which h as bean shown to elevate melatonin production, also decreased the levels of non-esterified AA and cPLA(2) mRNA significantly. Direct administration of melatonin to rats by intravenous injection decreased the levels of noneste rified AA, cPLA(2) protein and mRNA in rat pineal glands. In conclusion, me latonin endogenously down-regulates cPLA(2) expression, presumably through melatonin-receptor-mediated processes.