Mechanical stretch increases L-type calcium channel stability in cardiomyocytes through a polycystin-1/AKT-dependent mechanism
Author
dc.contributor.author
Córdova, Andrés
Author
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Olmedo, Ivonne
Author
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Riquelme, J.
Author
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Barrientos, G.
Author
dc.contributor.author
Sánchez, G.
Author
dc.contributor.author
Gillette, Thomas G.
Author
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Lavandero González, Sergio
Author
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Chiong Lay, Mario
Author
dc.contributor.author
Donoso, P.
Author
dc.contributor.author
Pedrozo Cibils, Zully
Admission date
dc.date.accessioned
2018-07-23T20:42:28Z
Available date
dc.date.available
2018-07-23T20:42:28Z
Publication date
dc.date.issued
2018
Cita de ítem
dc.identifier.citation
BBA - Molecular Cell Research 1865 (2018) 289–296
es_ES
Identifier
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10.1016/j.bbamcr.2017.11.001
Identifier
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https://repositorio.uchile.cl/handle/2250/150173
Abstract
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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 Cav beta 2 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 G beta gamma 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 Gi beta gamma-AKT-Cav beta 2 pathway, suggesting a new mechanism for regulation of cardiac function.
es_ES
Patrocinador
dc.description.sponsorship
Fondo Nacional de Desarrollo Cientifico y Tecnologico, FONDECYT
1150887
1130407
1160704
Postdoctoral FONDECYT
3140449
3160298
FONDAP
15130011