Methylfolate modulates potassium evoked neuro-secretion: evidence for a role at the pteridine cofactor level of tyrosine 3-hydroxylase.
We have previously shown that 5-methyltetrahydrofolate influences neuro-secretion. The present study more precisely characterises the processes involved and considers one probable site of action. Focusing on the tyrosine-noradrenalin axis in cerebellum we showed 5-methyltetrahydrofolate causes a significant reduction in the apparent K+ evoked secretion of noradrenalin to only 12.9% of control release. Evidence supports the idea that this could actually be due to increased synthesis leading to; depletion of reserves, possibly through leakage, exocytotic inhibition via activation of presynaptic receptors or end product inhibition by noradrenalin at the pteridine cofactor level of tyrosine hydroxylase: a) concomitant decreased measurement of perfusate and intracellular tyrosine with released noradrenalin following 5-methyltetrahydrofolate treatment supports the idea of increased transmitter turn over; b) kinetic studies indicate that at saturating concentrations of tyrosine and in the presence of an inhibitor of L-DOPA decarboxylase, 5-methyltetrahydrofolate partially duplicates the rate limiting behaviour of a synthetic pteridine cofactor--DL,2-amino-4-hydroxy-6,7,dimethyltetrahydropteridine. We debate whether, in vivo, CSF 5-methyltetrahydrofolate might interact at the tetrahydrobiopterin cofactor level of tyrosine hydroxylase and other aromatic amino-acid hydroxylases.
Lucock
M D
MD
University of Leeds, Department of Clinical Medicine, General Infirmary at Leeds, UK.
Green
M
M
Levene
M I
MI
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013763:Tetrahydrofolates / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D013763:Tetrahydrofolates; D001708:Biopterins; D014443:Tyrosine; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin; D011188:Potassium; C005984:5-methyltetrahydrofolate; D009638:Norepinephrine