THE TRANSCRIPTION OF A MAMMALIAN VOLTAGE-GATED POTASSIUM CHANNEL IS REGULATED BY CAMP IN A CELL-SPECIFIC MANNER

The transcript of Kv1.5, a Shaker-like delayed rectifier K+ channel cl oned in our laboratory, is regulated in both tissue and developmentall y specific manners. In this study we characterized the 5'-flanking reg ion of the Kv1.5 gene. The gene lacks a canonical TATA box, has severa l transcription start sites, and the 5'-noncoding sequence is intronle ss. A cAMP response element (CRE) consensus signal was identified in t he 5'-noncoding region. cAMP regulates the expression of Kv1.5 gene in a cell-specific manner. In primary cardiac cells, cAMP induces a 6-fo ld increase in the steady state levels of Kv1.5 transcript. However, i n GH3 cells cAMP induces a 5-6-fold decrease in steady state levels of Kv1.5 transcript. The half-life of Kv1.5 transcript is 37 min and is not affected by cAMP. Nuclear run-on experiments show that in GH3 cell s, cAMP reduces the transcription rate of Kv1.5 gene. Transient transf ection assays using 5'-deletion mutations of Kv1.5 5'-flanking sequenc es revealed that the CRE located at +636 can confer the cAMP inducibil ity to Kv1.5 reporter gene constructs and binds to CRE-binding protein (CREB) and CRE modulator protein (CREM) in electromobility gel shift assays. Furthermore, KCl-induced depolarization can increase the stead y state levels of Kv1.5 transcript in primary atrial cells and decreas e it in GH3 cells. We conclude that cAMP and depolarization play an im portant role in regulating K+ channel expression and thus may induce l ong term effects on the pattern of electrical activity of excitable ce lls.