Divergent signaling pathways mediate induction of Na,K-ATPase alpha1 and beta1 subunit gene transcription by low potassium.
Prolonged inhibition of Na,K-ATPase enzymatic activity by exposure of a variety of mammalian cells to low external K+ yields a subsequent adaptive up-regulation of Na,K-ATPase expression. The aim of this study was to examine the intracellular signal transduction system that is responsible for mediating increased Na,K-ATPase subunit gene expression in primary cultures of neonatal rat cardiac myocytes. In this work, we show long-term inhibition of Na,K-ATPase function with 0.6 mM K+ resulted in hypertrophy of cardiac myocytes and augmentation of Na,K-ATPase alpha1 and beta1 subunit gene expression. Transient transfection experiments in neonatal rat cardiac myocytes demonstrated that low K+ induction of alpha1 and beta1 gene transcription was dependent on intracellular Ca2+ and activation of calcineurin. Based on effects of pharmacological inhibitors, protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2) and histone deacetylase were found to be unique downstream components in the low K+ signal transduction pathway leading to increased alpha1 subunit promoter activity. Similarly, low K+-induced beta1 subunit gene transcription was dependent on activation of protein kinase C (PKC), c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These findings indicate that persistent inhibition of Na,K-ATPase activity with low external K+ activates overlapping and Na,K-ATPase subunit gene-specific signaling pathways in cardiac myocytes.
Wang
Gang
G
Department of Biochemistry and Center for Cardiovascular and Muscle Research, State University of New York Health Science Center at Brooklyn, NY 11203, USA.
Kawakami
Kiyoshi
K
Gick
Gregory
G
D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology*; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis* / Q000235:genetics*; D014158:Transcription, Genetic
D021122:Protein Subunits; D019703:Calcineurin; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D002118:Calcium