Elevated Ca2+ sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells

Manuel F. Navedo, Yukari Takeda, Madeline Nieves-Cintrón, Jeffery D. Molkentin, Luis F. Santana

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Ca+ sparklets are subcellular Ca2+ signals produced by the opening of L-type Ca2+ channels (LTCCs). In cerebral arterial myocytes, Ca2+ sparklet activity varies regionally, resulting in low and high activity, "persistent" Ca2+ sparklet sites. Although increased Ca2+ influx via LTCCs in arterial myocytes has been implicated in the chain of events contributing to vascular dysfunction during acute hyperglycemia and diabetes, the mechanisms underlying these pathological changes remain unclear. Here, we tested the hypothesis that increased Ca2+ sparklet activity contributes to higher Ca 2+ influx in cerebral artery smooth muscle during acute hyperglycemia and in an animal model of non-insulin-dependent, type 2 diabetes: the dB/dB mouse. Consistent with this hypothesis, acute elevation of extracellular glucose from 10 to 20 mM increased the density of low activity and persistent Ca 2+ sparklet sites as well as the amplitude of LTCC currents in wild-type cerebral arterial myocytes. Furthermore, Ca2+ sparklet activity and LTCC currents were higher in dB/dB than in control myocytes. We found that activation of PKA contributed to higher Ca2+ sparklet activity during hyperglycemia and diabetes. In addition, we found that the interaction between PKA and the scaffolding protein A-kinase anchoring protein was critical for the activation of persistent Ca2+ sparklets by PKA in cerebral arterial myocytes after hyperglycemia. Accordingly, PKA inhibition equalized Ca2+ sparklet activity between dB/dB and wild-type cells. These findings suggest that hyperglycemia increases Ca2+ influx by increasing Ca2+ sparklet activity via a PKA-dependent pathway in cerebral arterial myocytes and contributes to vascular dysfunction during diabetes.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume298
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

Keywords

  • Protein kinase A
  • Sparklets
  • Total internal reflection fluorescence microscopy

ASJC Scopus subject areas

  • Cell Biology
  • Physiology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Elevated Ca<sup>2+</sup> sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells'. Together they form a unique fingerprint.

  • Cite this