title: Modest CaV1.342-selective inhibition by compound 8 is β-subunit dependent.
abstract: Two voltage-gated calcium channel subtypes-CaV1.2 and CaV1.3-underlie the major L-type Ca(2+) 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.
authors: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors: Hua
authors: H
authors: Huang
authors: Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.
authors: Cheng Yang
authors: CY
authors: Ng
authors: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors: Dejie
authors: D
authors: Yu
authors: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors: Jing
authors: J
authors: Zhai
authors: Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.
authors: Yulin
authors: Y
authors: Lam
authors: 1] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore [2] NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore [3] Neurobiology/Ageing Programme, National University of Singapore, Singapore 117456, Singapore [4] National Neuroscience Institute, Jalan Tan Tock Seng, Singapore 308433, Singapore.
authors: Tuck Wah
authors: TW
authors: Soong
mesh_terms: D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D010328:Patch Tests; D020033:Protein Isoforms; D021122:Protein Subunits
chemical_list: C472073:CACNA1D protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020033:Protein Isoforms; D021122:Protein Subunits