REGULATION OF MESSENGER-RNA ENCODING 5-HT2A RECEPTORS IN P11 CELLS THROUGH A POSTTRANSCRIPTIONAL MECHANISM REQUIRING ACTIVATION OF PROTEIN-KINASE-C

Exposure of P11 cells to serotonin (5-HT) resulted in a transient incr ease 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 recept or mRNA. 5-HT-induced increases in receptor mRNA levels were not antag onized 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 mRN A 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 pho rbol 12-myristate 13-acetate (FMA), an activator of protein kinase C, mimicked these effects, whereas the protein kinase C inhibitor bisindo lyhmaleimide antagonized the effects of both 5-HT and PMA. When agonis t-promoted increases in receptor mRNA were prevented, the rate of agon ist-induced down-regulation was accelerated. These data suggest that l evels of 5-HT2A receptor mRNA are regulated by phospholipase C-coupled receptors via a protein kinase C-dependent, post-transcriptional mech anism and indicate that agonist-promoted increases in levels of 5-HT2A receptor mRNA modulate receptor expression.