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. Epub 2007 Apr 2.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caffeine / pharmacology
  • Calcium / metabolism*
  • Electrophysiology
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • TRPP Cation Channels / metabolism*

Substances

  • Ryanodine Receptor Calcium Release Channel
  • TRPP Cation Channels
  • polycystic kidney disease 2 protein
  • Caffeine
  • Calcium