ArticleThe Journal of biological chemistry2007
Probing the architecture of an L-type calcium channel with a charged phenylalkylamine: evidence for a widely open pore and drug trapping.
Article in The Journal of biological chemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Development of phenotypic assays for identifying novel blockers of L-type calcium channels in neurons.Scientific reports · 2021Article
- Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias.The Journal of innovations in cardiac rhythm management · 2019Review
- Calcium channel gating.Pflugers Archiv : European journal of physiology · 2018Review
- Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?Current molecular pharmacology · 2015Review
- Interaction of diltiazem with an intracellularly accessible binding site on Ca(V)1.2.British journal of pharmacology · 2011Article
- Physicochemical properties of pore residues predict activation gating of Ca V1.2: a correlation mutation analysis.Pflugers Archiv : European journal of physiology · 2011Article
- Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.The Journal of general physiology · 2010Article
- Structural model for phenylalkylamine binding to L-type calcium channels.The Journal of biological chemistry · 2009Article
- Co-localization of putative calcium channels (phenylalkylamine-binding sites) on oil bodies in protoplasts from dark-grown sunflower seedling cotyledons.Plant signaling & behavior · 2009Article
- Coupled and independent contributions of residues in IS6 and IIS6 to activation gating of CaV1.2.The Journal of biological chemistry · 2009Article
- Introduction into Ca(v)2.1 of the homologous mutation of Ca(v)1.2 causing the Timothy syndrome questions the role of V421 in the phenotypic definition of P-type Ca(2+) channel.Pflugers Archiv : European journal of physiology · 2008Article
- Models of the structure and gating mechanisms of the pore domain of the NaChBac ion channel.Biophysical journal · 2008Article
- The auxiliary subunit gamma 1 of the skeletal muscle L-type Ca2+ channel is an endogenous Ca2+ antagonist.Proceedings of the National Academy of Sciences of the United States of America · 2007Article
- A molecular model of the inner pore of the Ca channel in its open state.Channels (Austin, Tex.)Article
- Current concepts and molecular mechanisms in pharmacogenetics of essential hypertension.Indian journal of pharmacologyReview
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Voltage-gated calcium channels are in a closed conformation at rest and open temporarily when the membrane is depolarized. To gain insight into the molecular architecture of Ca(v)1.2, we probed the closed and open conformations with the charged phenylalkylamine (-)devapamil ((-)qD888). To elucidate the access pathway of (-)D888 to its binding pocket from the intracellular side, we used mutations replacing a highly conserved Ile-781 by threonine/proline in the pore-lining segment IIS6 of Ca(v)1.2 (1). The shifted channel gating of these mutants (by 30-40 mV in the hyperpolarizing direction) enabled us to evoke currents with identical kinetics at different potentials and thus investigate the effect of the membrane potentials on the drug access per se. We show here that under these conditions the development of channel block by (-)qD888 is not affected by the transmembrane voltage. Recovery from block at rest was, however, accelerated at more hyperpolarized voltages. These findings support the conclusion that Ca(v)1.2 must be opening widely to enable free access of the charged (-)D888 molecule to its binding site, whereas drug dissociation from the closed channel conformation is restricted by bulky channel gates. The functional data indicating a location of a trapped (-)D888 molecule close to the central pore region are supported by a homology model illustrating that the closed Ca(v)1.2 is able to accommodate a large cation such as (-)D888.
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