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; Santana, Luis Fernando; Xiang, Yang; Nieves‐Cintrón, Madeline; Navedo, Manuel F.

doi:10.1172/jci124705

Cited by 40 publications

(88 citation statements)

References 64 publications

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“…This sensor detects dynamic changes in cAMP production (low FRET signal) and degradation (high FRET signal) 33 , 34 . Targeting of the ICUE3-PM to the plasma membrane of arterial myocytes has been confirmed 19 . Human male and female arterial myocytes were obtained from adipose arteries of patients undergoing gastric sleeve surgery (Supplementary Table 1 ) 12 , 20 , 35 .…”

Section: Resultsmentioning

confidence: 89%

“…More than 89% of these unpassaged arterial myocyte cultures are positive for smooth muscle marker and negative for endothelial, macrophages or cell lineage markers ( n = 4 preparations; Supplementary Fig. 1b ) 19 , 20 . These results confirm the purity of the culture system.…”

Section: Resultsmentioning

confidence: 99%

“…P2Y 11 (in humans) or P2Y 11 -like (in rodents) receptors were identified as the G s protein-coupled receptor (G s PCR) triggering cAMP/PKA signaling, independent of any hetero-oligomerization with P2Y 1 or P2Y 6 receptors 20 , 21 . Intriguingly, super-resolution microscopy revealed pools of Ca V 1.2 in close association with subpopulations of P2Y 11 /P2Y 11 -like, AC5 and PKA in arterial myocytes 12 , 19 , 20 . Yet, how these proteins are spatially organized to efficiently restrict glucose signaling to regulate L-type Ca 2+ channel activity and vascular reactivity is unclear.…”

Section: Introductionmentioning

confidence: 96%

“…We recently discovered that glucose-induced PKA-dependent Ca V 1.2 phosphorylation, L-type Ca 2+ channel potentiation, and vasoconstriction required receptor-mediated subsarcolemmal cAMP production by adenylyl cyclase 5 (AC5) 19 . P2Y 11 (in humans) or P2Y 11 -like (in rodents) receptors were identified as the G s protein-coupled receptor (G s PCR) triggering cAMP/PKA signaling, independent of any hetero-oligomerization with P2Y 1 or P2Y 6 receptors 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

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AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2

et al. 2020

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The L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2

et al. 2020

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“…Irrespectively of this however, PKA signaling has been generally linked with vasodilation, thus raising questions about the functional relevance, if any, of this kinase in the regulation of vascular LTCCs. Intriguingly, recent studies revealed that elevations in extracellular D-glucose (HG) potentiate LTCC activity via a G s /AC/PKA pathway in vascular smooth muscle [82][83][84][85]. This HG-induced PKA-dependent activation of LTCCs resulted in increased global [Ca 2+ ] i and vasoconstriction, thus providing the first example of a PKA-dependent pathway underlying vascular smooth muscle contraction.…”

Section: L-type Ca 2+ Channel Camentioning

confidence: 99%

Ion Channels and Their Regulation in Vascular Smooth Muscle

Syed¹,

Le²,

Navedo³

et al. 2020

Basic and Clinical Understanding of Microcirculation

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Vascular smooth muscle excitability is exquisitely regulated by different ion channels that control membrane potential (E m) and the magnitude of intracellular calcium inside the cell to induce muscle relaxation or contraction, which significantly influences the microcirculation. Among them, various members of the K + channel family, voltage-gated Ca 2+ channels, and transient receptor potential (TRP) channels are fundamental for control of vascular smooth muscle excitability. These ion channels exist in complex with numerous signaling molecules and binding partners that modulate their function and, in doing so, impact vascular smooth muscle excitability. In this book chapter, we will review our current understanding of some of these ion channels and binding partners in vascular smooth muscle and discuss how their regulation is critical for proper control of (micro)vascular function.

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