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.

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

“…The loss of Na ϩ channel sensitivity to activity-induced internalization with development parallels the appearance during development of the ␤ 1 -subunit, implying a protective or stabilizing role for the ␤ 1 -subunit (6). As is the case for Kv1.5 downregulation in GH3 cells (328), Na ϩ channel internalization triggered by activity does not seem to be secondary to Ca 2ϩ influx (472). However, a similar endocytotic internalization of Na ϩ channels in chromaffin cells is mediated by increased [Ca 2ϩ ] i (294).…”

“…Activity can also show opposite effects on K ϩ channel expression in different cell types. Depolarization, acting via cAMP, upregulates Kv1.5 transcription in cardiac muscle but downregulates it in GH3 cells (328,427). [Interestingly, this effect in GH3 cells seems to be an unusual case in which the effects of activity are not secondary to Ca 2ϩ entry (328).]…”

“…Depolarization, acting via cAMP, upregulates Kv1.5 transcription in cardiac muscle but downregulates it in GH3 cells (328,427). [Interestingly, this effect in GH3 cells seems to be an unusual case in which the effects of activity are not secondary to Ca 2ϩ entry (328).] The effects of activity on K ϩ channel expression are likely to be due to several mechanisms, including transcriptional (328,427), mRNA stability (7), or with multiple posttranscriptional effects probably acting simultaneously in the same cell (66).…”

Perinatal hypoxia triggers alterations in K+channels of adult pulmonary artery smooth muscle cells

“…In fetal life, the physiological hypoxic environment causes inhibition of K Ca channels, resulting in PASMC depolarization contributing to the constricted state of PA (11). Prolonged depolarization has been shown to downregulate K V channel expression (24), providing an additional pathway by which K V channel activity may be modulated in the constricted fetal pulmonary circulation. At birth, O 2 induces PASMC hyperpolarization by activation of K Ca channels (10), leading to a decrease in [Ca 2ϩ ] i (34,41) and to PA vasodilatation (10,34).…”

Hypoxia Regulates Expression and Activity of Kv1.3 Channels in T Lymphocytes: A Possible Role in T Cell Proliferation

“…It is possible that the membrane depolarization or other events triggered by the inhibition of the activity of Kv1.3 channels in T cells can ultimately regulate its protein expression. Expression of another member of the Kv1 family, Kv1.5, was shown to be down-regulated by membrane depolarization in pituitary cells (49).…”