Hydroxyindole- O-methyltransferase is another target for l-glutamate-evoked inhibition of melatonin synthesis in rat pinealocytes

Abstract

Rat pinealocytes use l-glutamate as a modulator for melatonin synthesis. Upon binding of l-glutamate to the class II metabotropic glutamate receptor, norepinephrine (NE)-dependent formation of cAMP was inhibited, resulting in decreased serotonin- N-acetyltransferase (NAT) activity and melatonin output. Although l-glutamate at 1 mM caused 90% inhibition of melatonin synthesis, about 30% of the NAT activity remained, suggesting the presence of another target for l-glutamate. In this study, we found that l-glutamate also inhibits hydroxyindole- O-methyltransferase (HIOMT). The inhibition is reversible and dose-dependent: the maximal inhibition was obtained with more than 0.4 mM l-glutamate. Contrary to l-glutamate-evoked inhibition of NAT, agonists for class II metabotropic receptors such as (2 S,2′ R,3′ R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG IV) had no effect on HIOMT. Neither (2 S,3 S,4 S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG), an specific antagonist for class II mGluRs, nor dibutyryl cAMP restored the l-glutamate-evoked inhibition of HIOMT. Northern blot analyses revealed that l-glutamate significantly inhibits the expression of mRNA of NAT, but not that of HIOMT. These results indicated that HIOMT is an another target for l-glutamate due to its inhibition of melatonin synthesis, and the signaling pathway toward the inhibition is distinct from that of NAT.