Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel Cav1.2 and vasoconstriction during acute hyperglycemia and diabetes

Matthew A. Nystoriak, Madeline Nieves-Cintrón, Tommaso Patriarchi, Olivia R. Buonarati, Maria Paz Prada, Stefano Morotti, Eleonora Grandi, Julia Dos Santos Fernandes, Katherine Forbush, Franz Hofmann, Kent C. Sasse, John D. Scott, Sean M. Ward, Johannes W. Hell, Manuel F. Navedo

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37 Scopus citations

Abstract

Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type CaV1.2 channels. In murine arterial myocytes, kinasedependent mechanisms mediate the increase in CaV1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the CaV1.2 channel pore-forming subunit (α1C) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes. This arrangement depended upon scaffolding of PKA by an A-kinase anchoring protein 150 (AKAP150) in mice. Glucose-mediated increases in CaV1.2 channel activity were associated with PKA activity, leading to α1C phosphorylation at Ser1928. Compared to arteries from low-fat diet (LFD)-fed mice and nondiabetic patients, arteries from high-fat diet (HFD)-fed mice and from diabetic patients had increased Ser1928 phosphorylation and CaV1.2 activity. Arterial myocytes and arteries from mice lacking AKAP150 or expressing mutant AKAP150 unable to bind PKA did not exhibit increased Ser1928 phosphorylation and CaV1.2 current density in response to increased glucose or to HFD. Consistent with a functional role for Ser1928 phosphorylation, arterial myocytes and arteries from knockin mice expressing a CaV1.2 with Ser1928 mutated to alanine (S1928A) lacked glucose-mediated increases in CaV1.2 activity and vasoconstriction. Furthermore, the HFD-induced increases in CaV1.2 current density and myogenic tone were prevented in S1928A knockin mice. These findings reveal an essential role for α1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes.

Original languageEnglish (US)
Article numberaaf9647
JournalScience Signaling
Volume10
Issue number463
DOIs
StatePublished - Jan 24 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nystoriak, M. A., Nieves-Cintrón, M., Patriarchi, T., Buonarati, O. R., Prada, M. P., Morotti, S., Grandi, E., Fernandes, J. D. S., Forbush, K., Hofmann, F., Sasse, K. C., Scott, J. D., Ward, S. M., Hell, J. W., & Navedo, M. F. (2017). Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel Cav1.2 and vasoconstriction during acute hyperglycemia and diabetes. Science Signaling, 10(463), [aaf9647]. https://doi.org/10.1126/scisignal.aaf9647