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 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 Ca²⁺-independent inhibition of Kv1.5 gene transcription may produce a long-term enhancement of pituitary cell excitability and secretory activity.