Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism

• Published in: Biochimica et biophysica acta. Molecular cell research 2018-02, Vol.1865 (2), p.289-296
• Main Authors: Córdova-Casanova, A., Olmedo, I., Riquelme, J.A., Barrientos, G., Sánchez, G., Gillette, T.G., Lavandero, S., Chiong, M., Donoso, P., Pedrozo, Z.
• Format: Article
• Language: English
• Subjects: Animals; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Cav1.2; Cavβ; G-protein coupled receptor; Heart; Myocytes, Cardiac - metabolism; Neonatal rat ventricular myocytes; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rats; Signal Transduction; Stress, Mechanical; TRPP Cation Channels - genetics; TRPP Cation Channels - metabolism
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2017.11.001

The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells. We recently reported that PC1 regulates LTCC stability in cardiomyocytes under stress; however, the mechanism underlying this effect remains unknown. Here, we use cultured neonatal rat ventricular myocytes and hypo-osmotic stress (HS) to model mechanical stretch. The model shows that the Cavβ2 subunit is necessary for LTCC stabilization in cardiomyocytes during mechanical stretch, acting through an AKT-dependent mechanism. Our data also shows that AKT activation depends on the G protein-coupled receptor activity of PC1, specifically its G protein-binding domain, and the associated Gβγ subunit of a heterotrimeric Gi/o protein. In fact, over-expression of the human PC1 C-terminal mutant lacking the G protein-binding domain blunted the AKT activation-induced increase in Cav1.2 protein in cardiomyocytes. These findings provide novel evidence that PC1 is involved in the regulation of cardiac LTCCs through a Giβγ-AKT-Cavβ2 pathway, suggesting a new mechanism for regulation of cardiac function. [Display omitted] •During mechanical stretch AKT is activated by PC1.•Stabilization of Cav1.2 subunit requires AKT activation by PC1.•G protein domain of PC1 is necessary for the stabilization of Cav1.2.•Cavβ2 subunit is necessary for LTCC stabilization.