Regulation of phenylethanolamine N-methyltransferase gene expression by imidazoline receptors in adrenal chromaffin cells.
As adrenal medullary chromaffin cells express imidazoline binding sites in the absence of alpha 2-adrenergic receptors, these cells provide an ideal system in which to determine whether imidazolines can influence catecholamine gene expression through nonadrenergic receptors. This study evaluates the ability of clonidine and related drugs to regulate expression of the gene for the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT) in the rat adrenal gland and in bovine adrenal chromaffin cell cultures. In vivo, PNMT and tyrosine hydroxylase (TH) mRNA levels increase in rat adrenal medulla after a single injection of clonidine. Clonidine also dose-dependently stimulates PNMT mRNA expression in vitro in primary cultures of bovine chromaffin cells, with a threshold dose of 0.1 microM. Other putative imidazoline receptor agonists, including cimetidine, rilmenidine, and imidazole-4-acetic acid, likewise enhance PNMT mRNA production showing relative potencies that correlate with their binding affinities at chromaffin cell I1-imidazoline binding sites. The effects of clonidine on PNMT mRNA appear to be distinct from and additive with those exerted by nicotine. Moreover, neither nicotinic antagonists nor calcium channel blockers, which attenuate nicotine's influence on PNMT mRNA production, diminish clonidine's effects on PNMT mRNA. Although 100 microM clonidine diminishes nicotine-stimulated release of epinephrine and norepinephrine in chromaffin cells, this effect appears unrelated to stimulation of imidazoline receptor subtypes. This is the first report to link imidazoline receptors to neurotransmitter gene expression.
Evinger
M J
MJ
Department of Pediatrics, SUNY at Stony Brook 11794-8111, USA.
Ernsberger
P
P
Regunathan
S
S
Reis
D J
DJ
D000313:Adrenal Medulla / Q000201:enzymology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002838:Chromaffin System / Q000201:enzymology*; D003000:Clonidine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D054755:Imidazoline Receptors; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D054755:Imidazoline Receptors; D012333:RNA, Messenger; D011955:Receptors, Drug; D009538:Nicotine; D014446:Tyrosine 3-Monooxygenase; D010625:Phenylethanolamine N-Methyltransferase; D003000:Clonidine