Regulation of mRNA encoding 5-HT2A receptors in P11 cells through a post-transcriptional mechanism requiring activation of protein kinase C.
Exposure of P11 cells to serotonin (5-HT) resulted in a transient increase in levels of 5-HT2A receptor mRNA. Exposure to 5-HT for as short a time as 1 min was sufficient to trigger a delayed increase in receptor mRNA. 5-HT-induced increases in receptor mRNA levels were not antagonized by the protein synthesis inhibitor cycloheximide. The increase in receptor mRNA levels was accompanied by a transient increase in the half-life of receptor mRNA; the rate of transcription of receptor mRNA was unchanged. Submaximal stimulation of phosphinositide hydrolysis by partial agonists or 6-fluoronorepinephrine, an alpha 1-adrenergic receptor agonist, also increased receptor mRNA levels. Exposure to phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, mimicked these effects, whereas the protein kinase C inhibitor bisindolylmaleimide antagonized the effects of both 5-HT and PMA. When agonist-promoted increases in receptor mRNA were prevented, the rate of agonist-induced down-regulation was accelerated. These data suggest that levels of 5-HT2A receptor mRNA are regulated by phospholipase C-coupled receptors via a protein kinase C-dependent, post-transcriptional mechanism and indicate that agonist-promoted increases in levels of 5-HT2A receptor mRNA modulate receptor expression.
Ferry
R C
RC
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
Unsworth
C D
CD
Artymyshyn
R P
RP
Molinoff
P B
PB
D000591:Amino Acid Isomerases / Q000235:genetics; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008969:Molecular Sequence Data; D009638:Norepinephrine / Q000031:analogs & derivatives / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase; D010902:Pituitary Gland; D011493:Protein Kinase C / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011985:Receptors, Serotonin / Q000235:genetics*; D012701:Serotonin / Q000494:pharmacology; D014158:Transcription, Genetic
D000662:Amphetamines; D002352:Carrier Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D012701:Serotonin; C024884:6-fluoronorepinephrine; D008238:Lysergic Acid Diethylamide; D003513:Cycloheximide; D011493:Protein Kinase C; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D009638:Norepinephrine