Prolonged AT1R activation by AngII induces β-arrestin 1-mediated internalization of CaV1.2 channels, reducing L-type calcium currents and myocyte contractility, providing a novel mechanism for AngII-mediated cardiac remodeling.
Abstract The cardiac L-type calcium channel is a multi-subunit complex that requires co-assembling of the pore-forming subunit Ca V 1.2 with auxiliary subunits Ca V α 2 δ and Ca V β. Its traffic has been shown to be controlled by these subunits and by the activation of various G-protein coupled receptors (GPCR). Here, we explore the consequences of the prolonged activation of angiotensin receptor type 1 (AT 1 R) over Ca V 1.2 channel trafficking. Bioluminescence Resonance Energy Transfer (BRET) assay between β-arrestin and L-type channels in angiotensin II-stimulated cells was used to assess the functional consequence of AT 1 R activation, while immunofluorescence of adult rat cardiomyocytes revealed the effects of GPCR activation on Ca V 1.2 trafficking. Angiotensin II exposure results in β-arrestin 1 recruitment to the channel complex and an apparent loss of Ca V 1.2 immunostaining at the T-tubules. Accordingly, angiotensin II stimulation causes a decrease in L-type current, Ca 2+ transients and myocyte contractility, together with a faster repolarization phase of action potentials. Our results demonstrate that prolonged AT 1 R activation induces β-arrestin 1 recruitment and the subsequent internalization of Ca V 1.2 channels with a half-dose of AngII on the order of 100 nM, suggesting that this effect depends on local renin-angiotensin system. This novel AT 1 R-dependent Ca V 1.2-trafficking modulation likely contributes to angiotensin II-mediated cardiac remodeling.
Hermosilla et al. (Fri,) studied this question.