Sympathetic Stimulation Upregulates the Ca2+ Channel Subunit, CaVα2δ1, via the β1 and ERK 1/2 Pathway in Neonatal Ventricular Cardiomyocytes

Abstract

Intracellular Ca2+ overload secondary to chronic hemodynamic stimuli promotes the recruitment of Ca2+-dependent signaling implicated in cardiomyocyte hypertrophy. The present study tested the hypothesis that sympathetic-mediated hypertrophy of neonatal rat ventricular cardiomyocytes (NRVMs) translated to an increase in calcium influx secondary to the upregulation of CaV1.2 channel subunits. Confocal imaging of norepinephrine (NE)-treated NRVMs revealed a hypertrophic response compared to untreated NRVMs. L-type CaV1.2 peak current density was increased 4-fold following a 24-h stimulation with NE. NE-treated NRVMs exhibited a significant upregulation of CaVα2δ1 and CaVβ3 protein levels without significant changes of CaVα1C and CaVβ2 protein levels. Pre-treatment with the β1-blocker metoprolol failed to inhibit hypertrophy or CaVβ3 upregulation whereas CaVα2δ1 protein levels were significantly reduced. NE promoted the phosphorylation of ERK 1/2, and the response was attenuated by the β1-blocker. U0126 pre-treatment suppressed NE-induced ERK1/2 phosphorylation but failed to attenuate hypertrophy. U0126 inhibition of ERK1/2 phosphorylation prevented NE-mediated upregulation of CaVα2δ1, whereas CaVβ3 protein levels remained elevated. Thus, β1-adrenergic receptor-mediated recruitment of the ERK1/2 plays a seminal role in the upregulation of CaVα2δ1 in NRVMs independent of the concomitant hypertrophic response. However, the upregulation of CaVβ3 protein levels may be directly dependent on the hypertrophic response of NRVMs.

Non-canonical role of the sympathetic nervous system in the day–night rhythm in heart rate

“…Each of these signalling pathways can phosphorylate the ubiquitous transcription factor CREB, which promotes gene expression by binding to cAMP response elements (CREs) at target genes. Transcriptional regulation via these mechanisms has been reported for the L-type Ca 2+ channel subunits Cacna2d1 (Ca v α2δ) and Cacnb3 (Ca v β3) [ 32 ], and various K + channels, Kcna4 (K v 1.4), Kcna5 (K v 1.5), Kcnd2 (K v 4.2) and Kcnd3 (K v 4.3) [ 33 , 34 ]. This has not been investigated for Hcn4 , but conserved CRE motifs are enriched in its promoter region (data not shown).…”

Circadian regulation of CaV1.2 expression by RORα in the mouse heart

“…We next examined the effect of pharmacological activation and inhibition of RORα in vitro . After serum synchronization, isolated ventricular myocytes from 3 PCa-luc mice were kept in culture in the absence or the presence of either SR1078, a specific RORα agonist 43 or SR3335, a RORα inverse agonist 44 and luciferase activities were measured 24 h later. As shown in Fig.…”

“…In ventricular myocytes of diurnal guinea-pig, a Clock - Bmal1 -dependant circadian variation of Ca V 1.2 proteins through PI3K-Akt pathway was associated with simultaneous larger I CaL at ZT3 than at ZT15, but without diurnal variations of Cacna1c transcripts 35 . Conversely, Ca V 1.2 currents, mRNA and protein expressions peaked during the night under the control of Erk- and PI3K-Akt signaling pathways in embryo chick hearts 32 but mRNA and protein expressions of Ca V 1.2 in WT and cardiomyocyte-specific Clock mutant mouse heart remained constant throughout the day 33 whereas these pathways have been shown to regulate cardiac LTCCs 43, 45 . Our results showed both in vivo and in vitro in a mouse model (Fig.…”

Clinical Efficacy of Metoprolol Combined with Sacubitril/Valsartan in the Treatment of Chronic Heart Failure

“…receptor in human body, the contractility and agility of cardiomyocytes will be weakened under the effect of this index, which will lead to the failure of synthesis of Adenine Nucleoside Triphosphate (ATP), so as to achieve the purpose of regulation, avoid the synthesis of calcium ions and play an inhibitory role in toxins [15] . Metoprolol inhibits the proliferation of β3 receptors and enhances β1 division [16] . In addition, through the understanding of the medication mechanism of metoprolol, it can effectively block the sympathetic nerve pathway, thus destroying the negative feedback regulation of heart rate disorder, slowing down the malignant process, and promoting the reduction of NT-proBNP index [17] .…”