Hydroxyindole-O-methyltransferase is another target for L-glutamate-evokedinhibition of melatonin synthesis in rat pinealocytes

Rat pinealocytes use L-glutamate as a modulator for melatonin synthesis. Up on 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 outpu t. Although L-glutamate at 1 mM caused 90% inhibition of melatonin synthesi s, about 30% of the NAT activity remained, suggesting the presence of anoth er target for L-glutamate. In this study, we found that L-glutamate also in hibits hydroxyindole-O-methyltransferase (HIOMT). The inhibition is reversi ble and dose-dependent: the maximal inhibition was obtained with more than 0.4 mM L-glutamate. Contrary to L-glutamate-evoked inhibition of NAT, agoni sts for class Il metabotropic receptors such as (2S,2'R,3'R)-2-(2',3'-dicar boxycyclopropyl)glycine (DCG IV) had no effect on HIOMT. Neither (2S,3S,4S) -2-methyl-2-(carboxycyclopropyl)glycine (MCCG), an specific antagonist for class II mGluRs, nor dibutyryl cAMP restored the L-glutamate-evoked inhibit ion of HIOMT. Northern blot analyses revealed that L-glutamate significantl y inhibits the expression of mRNA of NAT, but not that of HIOMT. These resu lts indicated that HIOMT is an another target for L-glutamate due to its in hibition of melatonin synthesis, and the signaling pathway toward the inhib ition is distinct from that of NAT. (C) 1999 Elsevier Science B.V. All righ ts reserved.