| Summary: | Intracellular Ca<sup>2+</sup> overload secondary to chronic hemodynamic stimuli promotes the recruitment of Ca<sup>2+</sup>-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 Ca<sub>V</sub>1.2 channel subunits. Confocal imaging of norepinephrine (NE)-treated NRVMs revealed a hypertrophic response compared to untreated NRVMs. L-type Ca<sub>V</sub>1.2 peak current density was increased 4-fold following a 24-h stimulation with NE. NE-treated NRVMs exhibited a significant upregulation of Ca<sub>V</sub>α2δ1 and Ca<sub>V</sub>β3 protein levels without significant changes of Ca<sub>V</sub>α1C and Ca<sub>V</sub>β2 protein levels. Pre-treatment with the β<sub>1</sub>-blocker metoprolol failed to inhibit hypertrophy or Ca<sub>V</sub>β3 upregulation whereas Ca<sub>V</sub>α2δ1 protein levels were significantly reduced. NE promoted the phosphorylation of ERK 1/2, and the response was attenuated by the β<sub>1</sub>-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 Ca<sub>V</sub>α2δ1, whereas Ca<sub>V</sub>β3 protein levels remained elevated. Thus, β<sub>1</sub>-adrenergic receptor-mediated recruitment of the ERK1/2 plays a seminal role in the upregulation of Ca<sub>V</sub>α2δ1 in NRVMs independent of the concomitant hypertrophic response. However, the upregulation of Ca<sub>V</sub>β3 protein levels may be directly dependent on the hypertrophic response of NRVMs.
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