Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.
Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.
Takeda
Toshihiro
T
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Asahi
Michio
M
Yamaguchi
Osamu
O
Hikoso
Shungo
S
Nakayama
Hiroyuki
H
Kusakari
Yoichiro
Y
Kawai
Makoto
M
Hongo
Kenichi
K
Higuchi
Yoshiharu
Y
Kashiwase
Kazunori
K
Watanabe
Tetsuya
T
Taniike
Masayuki
M
Nakai
Atsuko
A
Nishida
Kazuhiko
K
Kurihara
Satoshi
S
Donoviel
Dorit B
DB
Bernstein
Alan
A
Tomita
Taisuke
T
Iwatsubo
Takeshi
T
Hori
Masatsugu
M
Otsu
Kinya
K
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010210:Papillary Muscles / Q000473:pathology; D010641:Phenotype; D053766:Presenilin-2; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction; D013599:Systole; D013997:Time Factors; D014162:Transfection
D002135:Calcium-Binding Proteins; D018076:DNA, Complementary; D007476:Ionophores; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D019837:Ryanodine Receptor Calcium Release Channel; C503114:Sri protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium