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Adenylyl cyclase 5–generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia
Arsalan U. Syed, … , Madeline Nieves-Cintrón, Manuel F. Navedo
Arsalan U. Syed, … , Madeline Nieves-Cintrón, Manuel F. Navedo
Published June 4, 2019
Citation Information: J Clin Invest. 2019;129(8):3140-3152. https://doi.org/10.1172/JCI124705.
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Research Article Cell biology Vascular biology

Adenylyl cyclase 5–generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia

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Abstract

Elevated blood glucose (hyperglycemia) is a hallmark metabolic abnormality in diabetes. Hyperglycemia is associated with protein kinase A–dependent (PKA-dependent) stimulation of L-type Ca2+ channels in arterial myocytes resulting in increased vasoconstriction. However, the mechanisms by which glucose activates PKA remain unclear. Here, we showed that elevating extracellular glucose stimulates cAMP production in arterial myocytes, and that this was specifically dependent on adenylyl cyclase 5 (AC5) activity. Super-resolution imaging suggested nanometer proximity between subpopulations of AC5 and the L-type Ca2+ channel pore-forming subunit CaV1.2. In vitro, in silico, ex vivo, and in vivo experiments revealed that this close association is critical for stimulation of L-type Ca2+ channels in arterial myocytes and increased myogenic tone upon acute hyperglycemia. This pathway supported the increase in L-type Ca2+ channel activity and myogenic tone in 2 animal models of diabetes. Our collective findings demonstrate a unique role for AC5 in PKA-dependent modulation of L-type Ca2+ channel activity and vascular reactivity during acute hyperglycemia and diabetes.

Authors

Arsalan U. Syed, Gopireddy R. Reddy, Debapriya Ghosh, Maria Paz Prada, Matthew A. Nystoriak, Stefano Morotti, Eleonora Grandi, Padmini Sirish, Nipavan Chiamvimonvat, Johannes W. Hell, Luis F. Santana, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo

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Figure 8

Proposed model for role of AC5-mediated localized cAMP production in stimulation of L-type Ca2+ channels and vasoconstriction upon increases in extracellular glucose and in diabetes.

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Proposed model for role of AC5-mediated localized cAMP production in sti...
Schematic model of glucose-mediated, AC5-dependent regulation of L-type Ca2+ channel activity and vascular reactivity. In this model, elevations in extracellular glucose, through transport and metabolization (13), can activate a P2Y receptor coupled to Gs signaling via extracellular nucleotide signaling (22) to specifically stimulate AC5 activity and localized production of cAMP. As AC5 is in close proximity to CaV1.2, this cAMP microdomain may activate a pool of AKAP150-anchored PKA that is intimately associated with CaV1.2 to increase its phosphorylation at serine 1928, leading to enhanced channel activity. This will result in an elevation in [Ca2+]i that modulates arterial myocyte contraction and myogenic tone.
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