Molecular determinants of drug binding and action on L-type calcium channels.

  title={Molecular determinants of drug binding and action on L-type calcium channels.},
  author={Gregory H. Hockerman and Blaise Z. Peterson and Brian D. Johnson and W. A. Catterall},
  journal={Annual review of pharmacology and toxicology},
The crucial role of L-type Ca2+ channels in the initiation of cardiac and smooth muscle contraction has made them major therapeutic targets for the treatment of cardiovascular disease. L-type channels share a common pharmacological profile, including high-affinity voltage- and frequency-dependent block by the phenylalkylamines, the benz(othi)azepines, and the dihydropyridines. These drugs are thought to bind to three separate receptor sites on L-type Ca2+ channels that are allosterically linked… 

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The results define the structural basis for binding of dihydropyridines and phenylalkylamines at their distinct receptor sites on CaV channels and offer key insights into their fundamental mechanisms of action and differential therapeutic uses in cardiovascular diseases.

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Molecular Determinants of High Affinity Dihydropyridine Binding in L-type Calcium Channels (*)

Results support the hypothesis that transmembrane segments IIIS6 and IVS6 both contribute critical amino acid residues to the DHP receptor site and that Tyr-1048 within trans Membrane segment IIIS 6 is required for high affinity DHP binding, even though it is conserved between DHP-sensitive and -insensitive Ca channels.

Molecular Determinants of High Affinity Phenylalkylamine Block of L-type Calcium Channels (*)

Since these three critical amino acid residues are aligned on the same face of the putative IVS6 α-helix, it is proposed that they contribute to a receptor site in the pore that confers a high affinity block of L-type channels by(-)D888.

The IVS6 segment of the L‐type calcium channel is critical for the action of dihydropyridines and phenylalkylamines.

The results suggest that the IVS6 segment of the alpha1C subunit is critical for the high affinity interaction between the L‐type calcium channel and the calcium channel agonist Bay K 8644 and the two antagonists isradipine and devapamil.

Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, [125I]iodipine.

The concept of three subtypes of Ca2+ channels, represented by brain, heart, and skeletal-muscle isoreceptors for 1,4-dihydropyridines, is developed and a change in the channel architecture is induced by binding of D-cis-diltiazem to its drug receptor site, proven by target-size analysis of the channel in situ.

Calcium‐Channel Drugs: Structure‐Function Relationships and Selectivity of Action

  • D. Triggle
  • Biology, Chemistry
    Journal of cardiovascular pharmacology
  • 1991
Experimental evidence underlying the structure-activity relationships and the voltage-dependent behavior of 1.4-dihydro-pyridine structure exhibits both potent antagonistic and activator properties is reviewed.

Transfer of High Sensitivity for Benzothiazepines from L-type to Class A (BI) Calcium Channels*

The data suggest that the receptor domains for diltiazem and gallopamil have common but not identical molecular determinants in transmembrane segment IVS6 that are important for class A channel inactivation.

Distinct effects of mutations in transmembrane segment IVS6 on block of L-type calcium channels by structurally similar phenylalkylamines.

The different effects of the YAI mutations on the actions of (-)-D888, verapamil, and D600 indicate that these residues interact differently with these closely related drugs.

Molecular determinants of state-dependent block of Na+ channels by local anesthetics.

The results define the location of the local anesthetic receptor site in the pore of the Na+ channel and identify molecular determinants of the state-dependent binding of local anesthetics.

Calcium Binding in the Pore of L-type Calcium Channels Modulates High Affinity Dihydropyridine Binding (*)

It is demonstrated that high affinity Ca binding to the Glu residues in the SS1/SS2 segments of domains III and IV of α stabilizes the DHP receptor site in its high affinity state.