ArticleProceedings of the National Academy of Sciences of the United States of America1997
Construction of a high-affinity receptor site for dihydropyridine agonists and antagonists by single amino acid substitutions in a non-L-type Ca2+ channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 88 citations in OpenAlex.
- Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944.The Journal of general physiology · 2026Article
- T- and L-Type Calcium Channels Maintain Calcium Oscillations in the Murine Zona Glomerulosa.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology.Channels (Austin, Tex.) · 2023Review
- CRISPR-Mediated Single Nucleotide Polymorphism Modeling in Rats Reveals Insight Into Reduced Cardiovascular Risk Associated With MediterraneanHypertension (Dallas, Tex. : 1979) · 2020Article
- Mechanism of adrenergic CaNature · 2020Article
- Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking.The Journal of clinical investigation · 2019Article
- Molecular Determinants of the Differential Modulation of CaMolecular pharmacology · 2018Article
- PF-06526290 can both enhance and inhibit conduction through voltage-gated sodium channels.British journal of pharmacology · 2018Article
- L-Type Calcium Channels Modulation by Estradiol.Molecular neurobiology · 2017Review
- Proteolytic cleavage and PKA phosphorylation of αProceedings of the National Academy of Sciences of the United States of America · 2017Article
- Reduced density gradient as a novel approach for estimating QSAR descriptors, and its application to 1, 4-dihydropyridine derivatives with potential antihypertensive effects.Journal of molecular modeling · 2016Article
- Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation.British journal of pharmacology · 2015Article
- Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels.Molecular pharmacology · 2015Review
- 1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain.Pflugers Archiv : European journal of physiology · 2015Article
- The PDZ motif of the α1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart.The Journal of biological chemistry · 2015Article
- International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands.Pharmacological reviews · 2014Article
- Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity.Pflugers Archiv : European journal of physiology · 2014Article
- β-adrenergic regulation of the L-type Ca2+ channel does not require phosphorylation of α1C Ser1700.Circulation research · 2013Article
- Increased intracellular magnesium attenuates β-adrenergic stimulation of the cardiac Ca(V)1.2 channel.The Journal of general physiology · 2013Article
- Protein homeostasis as a therapeutic target for diseases of protein conformation.Current topics in medicinal chemistry · 2012Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The activity of L-type Ca2+ channels is increased by dihydropyridine (DHP) agonists and inhibited by DHP antagonists, which are widely used in the therapy of cardiovascular disease. These drugs bind to the pore-forming alpha1 subunits of L-type Ca2+ channels. To define the minimal requirements for DHP binding and action, we constructed a high-affinity DHP receptor site by substituting a total of nine amino acid residues from DHP-sensitive L-type alpha1 subunits into the S5 and S6 transmembrane segments of domain III and the S6 transmembrane segment of domain IV of the DHP-insensitive P/Q-type alpha1A subunit. The resulting chimeric alpha1A/DHPS subunit bound DHP antagonists with high affinity in radioligand binding assays and was inhibited by DHP antagonists with high affinity in voltage clamp experiments. Substitution of these nine amino acid residues yielded 86% of the binding energy of the L-type alpha1C subunit and 92% of the binding energy of the L-type alpha1S subunit for the high-affinity DHP antagonist PN200-110. The activity of chimeric Ca2+ channels containing alpha1A/DHPS was increased 3.5 +/- 0.7-fold by the DHP agonist (-)Bay K8644. The effect of this agonist was stereoselective as in L-type Ca2+ channels since (+) Bay K8644 inhibited the activity of alpha1A/DHPS. The results show conclusively that DHP agonists and antagonists bind to a single receptor site at which they have opposite effects on Ca2+ channel activity. This site contains essential components from both domains III and IV, consistent with a domain interface model for binding and allosteric modulation of Ca2+ channel activity by DHPs.
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