Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.
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.
Anyatonwu
Georgia I
GI
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
Estrada
Manuel
M
Tian
Xin
X
Somlo
Stefan
S
Ehrlich
Barbara E
BE
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004594:Electrophysiology; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000378:metabolism*
D002110:Caffeine; D002118:Calcium; D019837:Ryanodine Receptor Calcium Release Channel; D050396:TRPP Cation Channels