1. Academic Validation
  2. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2

Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2

  • Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6454-9. doi: 10.1073/pnas.0610324104.
Georgia I Anyatonwu 1 Manuel Estrada Xin Tian Stefan Somlo Barbara E Ehrlich
Affiliations

Affiliation

  • 1 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
Abstract

Mutations in polycystin-2 (PC2) cause autosomal dominant polycystic kidney disease. A function for PC2 in the heart has not been described. Here, we show that PC2 coimmunoprecipitates with the cardiac ryanodine receptor (RyR2) from mouse heart. Biochemical assays showed that the N terminus of PC2 binds the RyR2, whereas the C terminus only binds to RyR2 in its open state. Lipid bilayer electrophysiological experiments indicated that the C terminus of PC2 functionally inhibited RyR2 channel activity in the presence of calcium (CA(2+)). PKD2(-/-) cardiomyocytes had a higher frequency of spontaneous CA(2+) oscillations, reduced CA(2+) release from the sarcoplasmic reticulum stores, and reduced CA(2+) content compared with PKD2(+/+) cardiomyocytes. In the presence of caffeine, PKD2(-/-) cardiomyocytes exhibited decreased peak fluorescence, a slower rate of rise, and a longer duration of CA(2+) transients compared with PKD2(+/+). These data suggest that PC2 is important for regulation of RyR2 function and that loss of this regulation of RyR2, as occurs when PC2 is mutated, results in altered CA(2+) signaling in the heart.

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