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

Autor: Syed AU; Department of Pharmacology, University of California, Davis, Davis, California, USA., Reddy GR; Department of Pharmacology, University of California, Davis, Davis, California, USA., Ghosh D; Department of Pharmacology, University of California, Davis, Davis, California, USA., Prada MP; Department of Pharmacology, University of California, Davis, Davis, California, USA., Nystoriak MA; Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky, USA., Morotti S; Department of Pharmacology, University of California, Davis, Davis, California, USA., Grandi E; Department of Pharmacology, University of California, Davis, Davis, California, USA., Sirish P; Department of Internal Medicine, University of California, Davis, Davis, California, USA., Chiamvimonvat N; Department of Pharmacology, University of California, Davis, Davis, California, USA.; Department of Internal Medicine, University of California, Davis, Davis, California, USA.; VA Northern California Health Care System, Mather, California, USA., Hell JW; Department of Pharmacology, University of California, Davis, Davis, California, USA., Santana LF; Department of Physiology and Membrane Biology, University of California, Davis, Davis, California, USA., Xiang YK; Department of Pharmacology, University of California, Davis, Davis, California, USA.; VA Northern California Health Care System, Mather, California, USA., Nieves-Cintrón M; Department of Pharmacology, University of California, Davis, Davis, California, USA., Navedo MF; Department of Pharmacology, University of California, Davis, Davis, California, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2019 Jun 04; Vol. 129 (8), pp. 3140-3152. Date of Electronic Publication: 2019 Jun 04.
DOI: 10.1172/JCI124705
Abstrakt: Elevated blood glucose (hyperglycemia) is a hallmark metabolic abnormality in diabetes. Hyperglycemia is associated with protein kinase A (PKA)-mediated 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 two 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.
Databáze: MEDLINE