MEMBRANE DEPOLARIZATION INHIBITS KV1.5 VOLTAGE-GATED K+ CHANNEL GENE-TRANSCRIPTION AND PROTEIN EXPRESSION IN PITUITARY-CELLS

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 Ev1.4 and Rv2.1 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 Ca2+-independent inhibition of Kv1.5 gene transcription may produce a longterm enhancement of pituitary cell excitability and secretory activity.