AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2.
Maria Paz PradaArsalan U SyedGopireddy R ReddyMiguel A S Martín-Aragón BaudelVictor A Flores-TamezKent C SasseSean M WardPadmini SirishNipavan ChiamvimonvatPeter BartelsEamonn J DicksonJohannes W HellJohn D ScottLuis F SantanaYang Kevin XiangManuel F NavedoMadeline Nieves-CintronPublished in: Nature communications (2020)
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.
Keyphrases
- blood flow
- gene expression
- protein kinase
- blood glucose
- type diabetes
- endothelial cells
- dna methylation
- single cell
- blood pressure
- nuclear factor
- cell proliferation
- immune response
- metabolic syndrome
- risk factors
- genome wide
- pi k akt
- rna seq
- electronic health record
- weight loss
- skeletal muscle
- toll like receptor
- binding protein
- drug induced
- cord blood
- big data
- induced pluripotent stem cells
- wound healing