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

J Clin Invest. 2019 Jun 4;129(8):3140-3152. doi: 10.1172/JCI124705.

Abstract

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.

Keywords: Calcium channels; Cell Biology; Cyclases; Diabetes; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / metabolism*
  • Animals
  • Calcium Channels, L-Type / biosynthesis
  • Calcium Channels, L-Type / genetics
  • Cerebral Arteries / enzymology*
  • Cerebral Arteries / pathology
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diabetes Mellitus, Experimental / enzymology*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / pathology
  • Hyperglycemia / enzymology*
  • Hyperglycemia / genetics
  • Hyperglycemia / pathology
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology

Substances

  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Adenylyl Cyclases
  • adenylyl cyclase type V