Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia

Enhanced L-type Ca 2+ channel (LTCC) activity in arterial myocytes contributes to vascular dysfunction during diabetes. Modulation of LTCC activity under hyperglycemic conditions could result from membrane potential-dependent and independent mechanisms. We have demonstrated that elevations in extrac...

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Bibliographic Details
Published in:Channels (Austin, Tex.) Tex.), 2017-07, Vol.11 (4), p.340-346
Main Authors: Morotti, Stefano, Nieves-Cintrón, Madeline, Nystoriak, Matthew A., Navedo, Manuel F., Grandi, Eleonora
Format: Article
Language:English
Subjects:
Addendum
arterial myocytes
Calcium - metabolism
Calcium Channels, L-Type - metabolism
Calcium Signaling
Caveolin 1 - metabolism
Cerebral Arteries - physiology
diabetes
Diabetes Mellitus - metabolism
Diabetes Mellitus - physiopathology
Glucose - metabolism
Hyperglycemia - metabolism
Hyperglycemia - physiopathology
Intracellular Space - metabolism
ion channels
mathematical modeling
Membrane Potentials
Models, Biological
Myocytes, Smooth Muscle - metabolism
Protein Conformation
sensitivity analysis
Vasoconstriction
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Summary:Enhanced L-type Ca 2+ channel (LTCC) activity in arterial myocytes contributes to vascular dysfunction during diabetes. Modulation of LTCC activity under hyperglycemic conditions could result from membrane potential-dependent and independent mechanisms. We have demonstrated that elevations in extracellular glucose (HG), similar to hyperglycemic conditions during diabetes, stimulate LTCC activity through phosphorylation of Ca V 1.2 at serine 1928. Prior studies have also shown that HG can suppress the activity of K + channels in arterial myocytes, which may contribute to vasoconstriction via membrane depolarization. Here, we used a mathematical model of membrane and Ca 2+ dynamics in arterial myocytes to predict the relative roles of LTCC and K + channel activity in modulating global Ca 2+ in response to HG. Our data revealed that abolishing LTCC potentiation normalizes [Ca 2+ ] i , despite the concomitant reduction in K + currents in response to HG. These results suggest that LTCC stimulation may be the primary mechanism underlying vasoconstriction during hyperglycemia.
ISSN:1933-6950
1933-6969
DOI:10.1080/19336950.2017.1293220