Hydroxyindole-O-methyltransferase is another target for L-glutamate-evoked inhibition of melatonin synthesis in rat pinealocytes.
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 (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)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 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.
Ishio
S
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Yamada
H
H
Craft
C M
CM
Moriyama
Y
Y
D000121:Acetylserotonin O-Methyltransferase / Q000378:metabolism*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D015152:Blotting, Northern; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D008297:Male; D008550:Melatonin / Q000096:biosynthesis*; D010870:Pineal Gland / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D000121:Acetylserotonin O-Methyltransferase; D001191:Arylamine N-Acetyltransferase; D008550:Melatonin