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A PKA‐coupled purinergic receptor macromolecular complex anchored by AKAP150 potentiates L‐type Ca2+ channel activity and vasoconstriction in diabetic hyperglycemia

Enhanced contractility of vascular smooth muscle in response to elevated extracellular glucose (HG), the hallmark metabolic abnormality in diabetes, contributes to vascular dysfunction associated with cardiovascular complications, such as hypertension. We previously showed that activation of the cAMP‐dependent protein kinase (PKA) anchored by the scaffolding protein AKAP150 has been associated with potentiation of vascular L‐type CaV1.2 channel (LTCC) activity in vascular smooth muscle (VSM) during HG. Moreover, we found evidence implicating a nucleotide‐activated purinergic receptor as a key player in the PKA‐mediated potentiation of LTCC activity and increased vasoconstriction during HG. Here, we tested the hypothesis that a vascular purinergic receptor coupled to Gs exists in a macromolecular complex with AKAP150, PKA, and LTCCs that is necessary for PKA‐mediated LTCC stimulation and enhanced vasoconstriction by HG. Super resolution microscopy, proximity ligation assays, and co‐immunoprecipitation revealed that a purinergic receptor coupled to Gs associate and co‐localize with AKAP150 and LTCCs in wild type and human VSM. Using patch clamp electrophysiology and pressurized cerebral arterial diameter measurements we found that the increase in LTCC current and vasoconstriction in response to HG and a specific activator of this purinergic receptor were ameliorated in VSM from AKAP150 knock out mice. Altogether, our findings suggest a critical role for an AKAP150‐anchored macromolecular complex formed by a Gs‐coupled purinergic receptor, PKA and LTCC in PKA‐mediated stimulation of LTCC activity and vasoconstriction during HG.