NDLI: Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation*

Content Provider	PubMed Central
Author	Viktor, Yarotskyy Gao, Guofeng Du, Lei Ganapathi, Sindura B. Peterson, Blaise Z. Elmslie, Keith S.
Abstract	L-type (CaV1.2) 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.
Related Links	http://dx.doi.org/10.1074/jbc.M109.076448
Starting Page	43
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	1
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-01-01
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation

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Roscovitine Binds to Novel L-channel (CaV1.2) Sites That Separately Affect Activation and Inactivation*

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