期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 1, 页码 43-53出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.076448
关键词
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资金
- National Institutes of Health [HL074143]
- American Heart Association Predoctoral Fellowship [0715336U]
- Department of Anesthesiology at the Penn State College of Medicine
- Pennsylvania Department of Health using Tobacco Settlement Funds
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL074143] Funding Source: NIH RePORTER
L-type (Ca(V)1.2) calcium channel antagonists play an important role in the treatment of cardiovascular disease. (R)-Roscovitine, a trisubstituted purine, has been shown to inhibit L-currents by slowing activation and enhancing inactivation. This study utilized molecular and pharmacological approaches to determine whether these effects result from (R)-roscovitine binding to a single site. Using the S enantiomer, we find that (S)-roscovitine enhances inactivation without affecting activation, which suggests multiple sites. This was further supported in studies using chimeric channels comprised of N- and L-channel domains. Those chimeras containing L-channel domains I and IV showed (R)- roscovitine-induced slowed activation like that of wild type L-channels, whereas chimeric channels containing L-channel domain I responded to (R)-roscovitine with enhanced inactivation. We conclude that (R)-roscovitine binds to distinct sites on L-type channels to slow activation and enhance inactivation. These sites appear to be unique from other calcium channel antagonist sites that reside within domains III and IV and are thus novel sites that could be exploited for future drug development. Trisubstituted purines could become a new class of drugs for the treatment of diseases related to hyperfunction of L-type channels, such as Torsades de Pointes.
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