A region of N-type Ca2+ channel critical for blockade by the dihydropyridine amlodipine

Distinct properties of amlodipine and nicardipine block of the voltage-dependent Ca2+ channels Cav1.2 and Cav2.1 and the mutant channels Cav1.2/Dihydropyridine insensitive and Cav2.1/Dihydropyridine sensitive

“…However, the IC 50 value for block of Ca v 2.1 by amlodipine reported in this study is virtually identical to that reported Furukawa et al. A recent study (Miyashita et al, 2010) reported that amlodipine blocks Ca v 2.2 at low micromolar concentrations, and that this block is disrupted by mutation of a Met residue in IIIS5 to Lys. Thus, even in the Ca v 2.2 channel which is devoid of the canonical DHP binding site found in Ca v 1.2 channels, amlodipine appears to interact strongly with amino acids residues in domain IIIS5, suggesting that amlodipine interacts predominantly with amino acid residues within a binding pocket formed by transmembrane domains IIIS5, IIIS6, and IVS6.…”

Harnessing Human N‐type Ca2+ Channel Receptor by Identifying the Atomic Hotspot Regions for Its Structure‐Based Blocker Design

“…We performed docking of potent antagonists‐amlodipine, cilnidipine and nifedipine which are known to be effective NCC/LCC blockers. Experimentally, the binding site of the ligand sensing domain of the NCC receptor was reported by Miyashita et al 14. Furthermore, identical/similar ligand sensing residues of the LCC receptor with the corresponding NCC receptor residues were identified by sequence alignment techniques 19…”

“…Using Glide software, 20 Å cubic boxes were used as the search region within which ligands must fit in order to be scored. We also defined the binding site regions in the NCC as reported by Miyashita et al 14. OPLS_2005 (optimized potential for liquid simulation) all atom force field was used, and other parameters were kept at default for the Glide docking.…”

“…Many hotspots residues important for the binding of VGCC antagonists especially for L‐type Ca 2+ channel (LCC) was identified, and substantial progress has been made in characterizing its channel pore structure 14,15. If available computer models of S5‐P‐S6 TMhs are accurate for other Ca 2+ channels, including KcsA and Na + channel, then the predicted hot‐spot blocker sensing residues can be experimentally tested.…”

“…The second objective of the present study was to identify the antagonist hotspot binding site residues of the closed state of human NCC using its 3D structural model. Recently, amlodipine a potent DHP Ca 2+ channel antagonist was experimentally tested for NCC inhibitory activity and key residues at different TMhs were identified 14. Furukawa et al.…”