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

A Schuster; L Lacinová; N Klugbauer; H Ito; L Birnbaumer; F Hofmann

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

EMBO J. 1996 May 15;15(10):2365-70.

Authors

A Schuster¹, L Lacinová, N Klugbauer, H Ito, L Birnbaumer, F Hofmann

Affiliation

¹ Institut für Pharmakologie and Toxikologie de TU München, Germany.

PMID: 8665843
PMCID: PMC450166

Abstract

The current through the L-type calcium channel is inhibited and stimulated by distinct dihydropyridines at very low concentrations. The molecular determinants for the high affinity block and stimulation were investigated using chimeras between the class C and E calcium channels. Mutation of three amino acids in the last putative transmembrane segment (IVS6) of the alpha1C subunit decreased the affinity for (+)isradipine 100-fold without significantly affecting the basic properties of the expressed channel. Mutation of two of these three amino acids completely abolished the stimulatory effect of the calcium channel agonist Bay K 8644. These mutations only slightly affected the blocking efficacy of mibefradil and the phenylalkylamine devapamil. Three distinct but adjacently located amino acids mediated the high affinity block by devapamil. These 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.

Publication types

Comparative Study

MeSH terms

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology*
Amino Acid Sequence
Benzimidazoles / pharmacology*
Calcium / metabolism
Calcium Channel Blockers / pharmacology*
Calcium Channels / chemistry*
Calcium Channels / drug effects
Calcium Channels, L-Type
Cell Line
Humans
Ion Channel Gating / drug effects*
Isradipine / pharmacology*
Mibefradil
Molecular Sequence Data
Muscle Proteins / chemistry*
Muscle Proteins / drug effects
Protein Structure, Tertiary*
Recombinant Fusion Proteins / drug effects
Recombinant Fusion Proteins / metabolism
Sequence Alignment
Structure-Activity Relationship
Tetrahydronaphthalenes / pharmacology*
Transfection
Verapamil / analogs & derivatives*
Verapamil / pharmacology

Substances

Benzimidazoles
Calcium Channel Blockers
Calcium Channels
Calcium Channels, L-Type
Muscle Proteins
Recombinant Fusion Proteins
Tetrahydronaphthalenes
Mibefradil
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Verapamil
devapamil
Calcium
Isradipine