Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 15, Pages 6454-6459Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0610324104
Keywords
intracellular calcium channel; polycystic kidney disease; lipid bilayer; calcium imaging; cardiac cells
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Funding
- NIDDK NIH HHS [P50 DK057328, DK062635, F31 DK062635, P50 DK57328] Funding Source: Medline
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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 (Ca2+). Pkd2(-/-) cardiomyocytes had a higher frequency of spontaneous Ca2+ oscillations, reduced Ca2+ release from the sarcoplasmic reticulum stores, and reduced Ca2+ 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 Ca2+ 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 Ca2+ signaling in the heart.
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