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

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 Fernando Santana, Yang Kevin Xiang, Madeline Nieves-Cintrón, Manuel F Navedo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume130
DOIs
StatePublished - Jun 4 2019

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Hyperglycemia
Blood Vessels
Cyclic AMP-Dependent Protein Kinases
Muscle Cells
Glucose
Vasoconstriction
Computer Simulation
Blood Glucose
Animal Models
adenylyl cyclase type V

Keywords

  • Calcium channels
  • Cell Biology
  • Cyclases
  • Diabetes
  • Vascular Biology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Adenylyl cyclase 5-generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia. / Syed, Arsalan U.; Reddy, Gopireddy R.; Ghosh, Debapriya; Prada, Maria Paz; Nystoriak, Matthew A.; Morotti, Stefano; Grandi, Eleonora; Sirish, Padmini; Chiamvimonvat, Nipavan; Hell, Johannes W; Santana, Luis Fernando; Xiang, Yang Kevin; Nieves-Cintrón, Madeline; Navedo, Manuel F.

In: The Journal of clinical investigation, Vol. 130, 04.06.2019.

Research output: Contribution to journalArticle

Syed, Arsalan U. ; Reddy, Gopireddy R. ; Ghosh, Debapriya ; Prada, Maria Paz ; Nystoriak, Matthew A. ; Morotti, Stefano ; Grandi, Eleonora ; Sirish, Padmini ; Chiamvimonvat, Nipavan ; Hell, Johannes W ; Santana, Luis Fernando ; Xiang, Yang Kevin ; Nieves-Cintrón, Madeline ; Navedo, Manuel F. / Adenylyl cyclase 5-generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia. In: The Journal of clinical investigation. 2019 ; Vol. 130.
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