Sympathetic Stimulation Upregulates the Ca 2+ Channel Subunit, Ca V α2δ1, via the β1 and ERK 1/2 Pathway in Neonatal Ventricular Cardiomyocytes.

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