Endothelin-1 stimulates the expression of L-type Ca2+ channels in neonatal rat cardiomyocytes via the extracellular signal-regulated kinase 1/2 pathway.

The cardiac L-type Ca(2+) channel current (I(Ca,L)) plays an important role in controlling both cardiac excitability and excitation-contraction coupling and is involved in the electrical remodeling during postnatal heart development and cardiac hypertrophy. However, the possible role of endothelin-1 (ET-1) in the electrical remodeling of postnatal and diseased hearts remains unclear. Therefore, the present study was designed to investigate the transcriptional regulation of I(Ca,L) mediated by ET-1 in neonatal rat ventricular myocytes using the whole-cell patch-clamp technique, quantitative RT-PCR and Western blotting. Furthermore, we determined whether the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is involved. ET-1 increased I(Ca,L) density without altering its voltage dependence of activation and inactivation. In line with the absence of functional changes, ET-1 increased L-type Ca(2+) channel pore-forming α1C-subunit mRNA and protein levels without affecting the mRNA expression of auxiliary β- and α2/δ-subunits. Furthermore, an actinomycin D chase experiment revealed that ET-1 did not alter α1C-subunit mRNA stability. These effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 but not the ETB receptor antagonist BQ-788. Moreover, the effects of ET-1 on I(Ca,L) and α1C-subunit expression were abolished by the ERK1/2 inhibitor (PD98059) but not by the p38 MAPK inhibitor (SB203580) or the c-Jun N-terminal kinase inhibitor (SP600125). These findings indicate that ET-1 increased the transcription of L-type Ca(2+) channel in cardiomyocytes via activation of ERK1/2 through the ETA receptor, which may contribute to the electrical remodeling of heart during postnatal development and cardiac hypertrophy.