Wnt11/Fzd7 signaling compartmentalizes AKAP2/PKA to regulate L-type Ca2+ channel
Csalyi, K. D.; Rharass, T.; Schulz, M.; Phan, M. H.; Wakula, P.; Mhatre, K. N.; Plotnick, D.; Werdich, A. A.; Zauber, H.; Sury, M. D.; Selbach, M.; Heinzel, F. R.; Klussmann, E.; Panakova, D.
Show 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 {beta}-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 Ca2+ homeostasis.
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