Modest CaV1.342-selective inhibition by compound 8 is β-subunit dependent

Hua Huang, Cheng Yang Ng, Dejie Yu, Jing Zhai, Yulin Lam and Tuck Wah Soong ()
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Hua Huang: Yong Loo Lin School of Medicine, National University of Singapore
Cheng Yang Ng: National University of Singapore
Dejie Yu: Yong Loo Lin School of Medicine, National University of Singapore
Jing Zhai: Yong Loo Lin School of Medicine, National University of Singapore
Yulin Lam: National University of Singapore
Tuck Wah Soong: Yong Loo Lin School of Medicine, National University of Singapore

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: Abstract Two voltage-gated calcium channel subtypes—CaV1.2 and CaV1.3—underlie the major L-type Ca2+ currents in the mammalian central nervous system. Owing to their high sequence homology, the two channel subtypes share similar pharmacological properties, and at high doses classic calcium channel blockers, such as dihydropyridines, phenylalkylamines and benzothiazepines, do not discriminate between the two channel subtypes. Recent progress in treating Parkinson’s disease (PD) was marked by the discovery of synthetic compound 8, which was reported to be a highly selective inhibitor of the CaV1.3 L-type calcium channels (LTCC). However, despite a previously reported IC50 of ~24 μM, in our hands inhibition of the full-length CaV1.342 by compound 8 at 50 μM reaches a maximum of 45%. Moreover, we find that the selectivity of compound 8 towards CaV1.3 relative to CaV1.2B15 channels is greatly influenced by the β-subunit type and its splice isoform variants.

Date: 2014
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DOI: 10.1038/ncomms5481

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