The muscarinic receptor-binding properties of a series of muscarinic drugs were compared with their effects on adenylate cyclase in membranes of the rabbit myocardium. When measured by competitive inhibition of [3H]-N-methylscopolamine binding, the competition curves of the various agonists were adequately described by the ternary complex model. This model assumes that the receptor can bind reversibly with a guanine nucleotide binding protein in the membrane and that the affinity of the agonist for the receptor-guanine nucleotide-binding protein complex is higher than that for the free receptor. A satisfactory fit of the ternary complex model to the data could only be achieved assuming that very little receptor is precoupled with the guanine nucleotide-binding protein in the absence of agonist. There was good agreement between the efficacy of each agonist as measured by inhibition of adenylate cyclase and the estimate of the positive cooperativity between the binding of the agonist receptor complex and the guanine nucleotide-binding protein. Guanosine 5'-triphosphate (0.1 mM) had no significant effect on the binding of [3H]N-methylscopolamine but caused an increase in the concentration of the various agonists required for half-maximal receptor occupancy. There was good correlation between efficacy as measured by inhibition of adenylate cyclase and the influence of guanosine 5'-triphosphate on binding properties.
The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium.
Published 1985 in Molecular Pharmacology
ABSTRACT
PUBLICATION RECORD
- Publication year
1985
- Venue
Molecular Pharmacology
- Publication date
1985-11-01
- Fields of study
Medicine, Chemistry
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- [3h]-n-methylscopolamine binding
A tritiated radioligand binding assay used to quantify muscarinic receptor binding and occupancy.
Aliases: [3H]N-methylscopolamine binding, 3H-N-methylscopolamine binding
- adenylate cyclase inhibition
The functional assay readout used to measure how the tested agonists suppressed adenylate cyclase activity in myocardial membranes.
Aliases: inhibition of adenylate cyclase
- guanine nucleotide binding protein
A membrane-associated G protein that can reversibly couple to the receptor in the ternary complex framework.
Aliases: G protein, guanine nucleotide-binding protein
- guanosine 5'-triphosphate
A guanine nucleotide added at 0.1 mM to examine its effects on receptor binding behavior.
Aliases: GTP
- muscarinic agonists
Muscarinic drugs with agonist activity that were compared for binding and functional effects in rabbit myocardium.
Aliases: muscarinic drugs, agonists
- positive cooperativity
The cooperative interaction term describing enhanced agonist affinity when the receptor is associated with the guanine nucleotide binding protein.
Aliases: positive cooperativity between the binding of the agonist receptor complex and the guanine nucleotide binding protein
- receptor occupancy
The fraction of muscarinic receptors occupied by agonist under the binding conditions used in the assay.
Aliases: half-maximal receptor occupancy
- ternary complex model
A receptor signaling model in which the receptor can reversibly associate with a guanine nucleotide binding protein and show altered agonist affinity.
Aliases: ternary complex
REFERENCES
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