CREB critically regulates action potential shape and duration in the adult mouse ventricle

Abstract

FU. CREB critically regulates action potential shape and duration in the adult mouse ventricle. Am J Physiol Heart Circ Physiol 302: H1998 -H2007, 2012. First published March 16, 2012; doi:10.1152/ajpheart.00057.2011The cAMP response element binding protein (CREB) belongs to the CREB/ cAMP response element binding modulator/activating transcription factor 1 family of cAMP-dependent transcription factors mediating a regulation of gene transcription in response to cAMP. Chronic stimulation of ␤-adrenergic receptors and the cAMP-dependent signal transduction pathway by elevated plasma catecholamines play a central role in the pathogenesis of heart failure. Ion channel remodeling, particularly a decreased transient outward current (Ito), and subsequent action potential (AP) prolongation are hallmarks of the failing heart. Here, we studied the role of CREB for ion channel regulation in mice with a cardiomyocyte-specific knockout of CREB (CREB KO). APs of CREB KO cardiomyocytes were prolonged with increased AP duration at 50 and 70% repolarization and accompanied by a by 51% reduction of I to peak amplitude as detected in voltageclamp measurements. We observed a 29% reduction of Kcnd2/Kv4.2 mRNA in CREB KO cardiomyocytes mice while the other I to-related channel subunits Kv4.3 and KChIP2 were not different between groups. Accordingly, Kv4.2 protein was reduced by 37% in CREB KO. However, we were not able to detect a direct regulation of Kv4.2 by CREB. The I to-dependent AP prolongation went along with an increase of I Na and a decrease of ICa,L associated with an upregulation of Scn8a/Nav1.6 and downregulation of Cacna1c/Cav1.2 mRNA in CREB KO cardiomyocytes. Our results from mice with cardiomyocyte-specific inactivation of CREB definitively indicate that CREB critically regulates the AP shape and duration in the mouse ventricle, which might have an impact on ion channel remodeling in situations of altered cAMP-dependent signaling like heart failure. ion channel remodeling; heart; transcriptional regulation; adenosine 3=,5=-cyclic monophosphate response element binding protein; transient outward current

Feedback Mechanisms for Cardiac-Specific MicroRNAs and cAMP Signaling in Electrical Remodeling

“…48 Moreover, cardiacspecific knockout of CREB led to a 50% reduction in K v 4.2 resulting in a significant loss of peak I to and prolonged APDs even though the K v 4.2 promoter appears to lack a CRE sequence. 33 Our findings demonstrating that both CREM and ICER are direct targets of miR-1 may help explain these earlier results. Moreover, increased expression of ICER post MI leads to a reduction of miR-1 and -133 and the consequences of electrical remodeling.…”

“…32 In addition, cardiac-specific knockout of CREB led to electrical remodeling in cardiomyocytes similar to that seen post MI with a loss of I to and prolonged action potential durations (APDs). 33 Electrical remodeling has been well documented in cardiac hypertrophy and failure with down-regulation of K + currents and APD prolongation. 34 Moreover, recent studies have provided strong evidence for the critical roles of miRs in ion channel regulation.…”

Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation

“…By comparing the enriched motifs from the cardiac-TasR proximal promoter regions to known TFBS, we observed binding sites for common transcription factor families, including the basic helix-loophelix (bHLH) (e.g., nescient helix-loop-helix (Nhlh1) and myogenic factor 5 (Myf5)) and the basic leucine zipper (bZIP) families (e.g., CREB and CCAAT-enhancer-binding protein (C/EBP)). These ubiquitous transcription factors have been broadly implicated in physiology and disease, including in the cardiovascular system (Fentzke et al 1998;Conway et al 2010;Schauer et al 2010;Schulte et al 2012). In addition, studies interrogating Nhlh1 (Cogliati et al 2002) and…”

Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates

“…L-type Ca 2ϩ Channel Currents-Single cardiomyocytes were studied using the perforated patch whole cell patch-clamp technique as described previously (24). Recordings were performed under conditions that suppress Na ϩ and K ϩ currents.…”

“…Quantitative RT-PCR-Total quantification of mRNA levels was performed as described previously with following modifications (24). Briefly, RNA was extracted from isolated cardiomyocytes with the use of TRIzol (Invitrogen), and 0.5 g were randomly reversely transcribed to cDNA using the Transcriptor First Strand cDNA synthesis kit (Roche Applied Science).…”