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Wnt11/Fzd7 signaling compartmentalizes AKAP2/PKA to regulate L-type Ca(2+) channel

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Item Type:Preprint
Title:Wnt11/Fzd7 signaling compartmentalizes AKAP2/PKA to regulate L-type Ca(2+) channel
Creators Name:Csalyi, K.D. and Rharass, T. and Schulz, M. and Phan, M.H.Q. and Wakula, P. and Mhatre, K.N. and Plotnick, D. and Werdich, A.A. and Zauber, H. and Sury, M.D. and Selbach, M. and Heinzel, F.R. and Klussmann, E. and Panakova, D.
Abstract:Calcium influx through the voltage-gated L-type calcium channels (LTCC) mediates a wide range of physiological processes from contraction to secretion. Despite extensive research on regulation of LTCC conductance by PKA phosphorylation in response to β-adrenergic stimulation, the science remains incomplete. Here, we show that Wnt11, a non-canonical Wnt ligand, through its G protein-coupled receptor (GPCR) Fzd7 attenuates the LTCC conductance by preventing the proteolytic processing of its C terminus. This is mediated across species by protein kinase A (PKA), which is compartmentalized by A-kinase anchoring proteins (AKAP). Systematic analysis of all AKAP family members revealed AKAP2 anchoring of PKA is central to the Wnt11-dependent regulation of the channel. The identified Wnt11/AKAP2/PKA signalosome is required for heart development, controlling the intercellular electrical coupling in the developing zebrafish heart. Altogether, our data revealed Wnt11/Fzd7 signaling via AKAP2/PKA as a conserved alternative GPCR system regulating Ca(2+) homeostasis.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:741637
Date:20 August 2019
Official Publication:https://doi.org/10.1101/741637

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