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

Authors: Maria Paz Prada, Arsalan U Syed, Gopireddy R Reddy, Miguel Martín-Aragón Baudel, Víctor A Flores-Tamez, Kent C Sasse, Sean M Ward, Padmini Sirish, Nipavan Chiamvimonvat, Peter Bartels, Eamonn J Dickson, Johannes W Hell, John D Scott, Luis F Santana, Yang K Xiang, Manuel F Navedo, Madeline Nieves-Cintrón

Journal, date & volume: Nat Commun, 2020Oct20, 11, 5303

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/33082339

Abstract
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.