Wnt11/Fzd7 signaling compartmentalizes AKAP2/PKA to regulate L-type Ca2+ channel

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

Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca(2+) channel

Electrical gradients are critical for many biological processes, including the normal function of excitable tissues, left-right patterning, organogenesis and wound healing. The fundamental mechanisms that regulate the establishment and maintenance of such electrical polarities are poorly understood. Here we identify a gradient of electrical coupling across the developing ventricular myocardium using high-speed optical mapping of transmembrane potentials and calcium concentrations in the zebrafish heart. We excluded a role for differences in cellular excitability, connexin localization, tissue geometry and mechanical inputs, but in contrast we were able to demonstrate that non-canonical Wnt11 signals are required for the genesis of this myocardial electrical gradient. Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca(2+) conductance mediated by the L-type calcium channel. These data reveal a previously unrecognized role for Wnt/Ca(2+) signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function. The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals

Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy

10.1016/j.ajhg.2013.05.015American Journal of Human Genetics93167-77AJHG