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1 Molecular Biology Division, Center for Basic Research, Foundation for Biomedical Research of the Academy of Athens, ATHENS, Attica, Greece
2 Athens, Attica, Greece; Molecular Biology Division, Center for Basic Research, Foundation for Biomedical Research of the Academy of Athens, ATHENS, Attica, Greece
3 Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, United States
4 Cincinnati, Ohio, United States; Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, United States
5 3Department of Cardiology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States
6 Physiology, University of Maryland Baltimore, Baltimore, Maryland, United States
7 Molecular Biology, Foundation for Biomedical Research, Academy of Athens, Athens, Greece
8 Pharmacology & Cell Biophysics, University of Cincinatti, Cincinnati, Ohio, United States; University of Cincinatti, United States
* To whom correspondence should be addressed. E-mail: litsa.kranias{at}uc.edu.
Depressed cardiac Ca-cycling by the sarcoplasmic reticulum (SR) has been associated with attenuated contractility, which can progress to heart failure. The histidine-rich calcium binding protein (HRC) is a SR component that binds to triadin and may affect Ca release through the ryanodine receptor. HRC overexpression in transgenic mouse hearts was associated with decreased rates of SR Ca uptake and delayed relaxation, which progressed to hypertrophy upon aging. The present study shows that HRC may mediate part of its regulatory effects by binding directly to SERCA2 in cardiac muscle. This interaction involves the histidine and glutamic acid-rich domain of HRC (320-460aa) and part of the N-terminal cation transporter domain of SERCA2 (74-90aa), which projects into the SR lumen. The SERCA2 binding domain is upstream from the triadin-binding region in human HRC (609-699aa). Specific binding between HRC and SERCA was verified by co-immunoprecipitation and pull-down assays using human and mouse cardiac homogenates, and by blot overlays with GST and MBP recombinant proteins. Importantly, increases in Ca concentration from 0.1 to 100 μM were associated with significant reduction of the HRC binding to SERCA2, while they had opposite effects on the interaction between HRC and triadin. Collectively, our data suggest that HRC may play a key role in the regulation of SR Ca-cycling through its direct interactions with SERCA2 and triadin, mediating a fine cross-talk between SR Ca uptake and release in the heart.
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