title: Membrane depolarization inhibits Kv1.5 voltage-gated K+ channel gene transcription and protein expression in pituitary cells.
abstract: Voltage-gated K+ channels play an essential role in the production of action potential activity by excitable cells. Recent studies have suggested that expression of K+ channel genes may be regulated by stimuli that affect electrical activity. Elevating the concentration of extracellular KCl causes membrane depolarization and, thus, is widely used for studying electrical activity-dependent changes in neurons, muscle, and endocrine cells. Here we show that elevated KCl decreases Kv1.5 K+ channel mRNA expression in clonal pituitary cells without affecting Kv1.4 and Kv2.1 mRNA levels. K+ channel blockers, which cause depolarization, also produce down-regulation of Kv1.5 mRNA, while NaCl addition had no effect. Thus, the effect of KCl is mediated by K(+)-induced membrane depolarization. Unlike many known effects of K+, down-regulation of Kv1.5 mRNA does not require Ca2+ or Na+ influx, or Na(+)-H+ exchange. Furthermore, the decrease in Kv1.5 mRNA expression is due to inhibition of channel gene transcription and persists after inhibition of protein synthesis, excluding a role for induction of intermediary regulatory proteins. Finally, immunoblots with antibody specific for the Kv1.5 polypeptide show that depolarization for 8 h reduces the expression of Kv1.5 channel protein. The decrease in K+ channel protein expression caused by depolarization-induced Ca(2+)-independent inhibition of Kv1.5 gene transcription may produce a long-term enhancement of pituitary cell excitability and secretory activity.
authors.affiliation: Department of Pharmacology, University of Pittsburgh, Pennsylvania 15261.
authors.forename: E S
authors.initials: ES
authors.lastname: Levitan
authors.forename: R
authors.initials: R
authors.lastname: Gealy
authors.forename: J S
authors.initials: JS
authors.lastname: Trimmer
authors.forename: K
authors.initials: K
authors.lastname: Takimoto
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002999:Clone Cells; D015536:Down-Regulation / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D051666:Kv1.5 Potassium Channel; D008536:Meglumine / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D010911:Pituitary Neoplasms; D015221:Potassium Channels / Q000096:biosynthesis*; D024642:Potassium Channels, Voltage-Gated; D011189:Potassium Chloride / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D009553:Nimodipine; D011189:Potassium Chloride; D008536:Meglumine; D000584:Amiloride; D012964:Sodium; D009543:Nifedipine; D002118:Calcium