Prolonged AT(1)R activation induces Ca(V)1.2 channel internalization in rat cardiomyocytes

作者：Hermosilla Tamara; Encina Matias; Morales Danna; Moreno Cristian; Conejeros Carolina; Alfaro Valdes Hilda M; Lagos Meza Felipe; Simon Felipe; Altier Christophe; Varela Diego^*

来源：Scientific Reports, 2017, 7(1): 10131.

DOI：10.1038/s41598-017-10474-z

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 alpha 2 delta and Ca-V beta. 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 beta-arrestin and L-type channels in angiotensin II-stimulated cells was used to assess the functional consequence of AT1R activation, while immunofluorescence of adult rat cardiomyocytes revealed the effects of GPCR activation on Ca(V)1.2 trafficking. Angiotensin II exposure results in beta-arrestin1 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, Ca2+ transients and myocyte contractility, together with a faster repolarization phase of action potentials. Our results demonstrate that prolonged AT1R activation induces beta-arrestin 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.

• 出版日期2017-8-31