Effects of agonist efficacy on desensitization of phosphoinositide hydrolysis mediated by m1 and m3 muscarinic receptors expressed in Chinese hamster ovary cells
- Department of Pharmacology and Toxicology, University of Maryland School of Pharmacy, Baltimore (USA)
Muscarinic receptor agonist-induced desensitization of phosphoinositide (PI) hydrolysis and loss of receptors were studied in Chinese hamster ovary (CHO) cells transfected with the m1 and m3 muscarinic receptor genes. Long-term exposure to the full agonist carbamylcholine (CBC) resulted in a time-dependent attenuation of the maximal PI response and a decrease in agonist potency. This desensitization was accompanied by a parallel loss of maximal ligand binding without an alteration of the binding affinity. The time course of both receptor desensitization and down-regulation was similar in m1 and m3 CHO cells. The PI response to the partial agonist McN-A-343 (McN) in m1 cells was more sensitive to desensitization by CBC than the response to the latter agonist, and this desensitization was faster than receptor down-regulation. Desensitization of the PI response to McN was reflected as a decrease in the maximal response without a marked change in potency. McN induced slow desensitization of the PI response to CBC but a much faster desensitization of its own response. Our data provide evidence that although muscarinic agonist-induced desensitization of PI hydrolysis in CHO cells is due mainly to loss of receptors, there are other important factors which play a role in this process, e.g., receptor-effector uncoupling. The relative contribution of these different mechanisms depends on the efficacy of the agonists used for the receptor desensitization and activation steps.
- OSTI ID:
- 5398169
- Journal Information:
- Journal of Pharmacology and Experimental Therapeutics; (United States), Journal Name: Journal of Pharmacology and Experimental Therapeutics; (United States) Vol. 257:3; ISSN 0022-3565; ISSN JPETA
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
AFFINITY
ANIMAL CELLS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BIOCHEMICAL REACTION KINETICS
CHEMICAL REACTIONS
CHO CELLS
DECOMPOSITION
DRUGS
ESTERS
GENES
HAMSTERS
HYDROGEN COMPOUNDS
HYDROLYSIS
KINETICS
LIGANDS
LIPIDS
LYSIS
MAMMALS
MEMBRANE PROTEINS
METABOLISM
ORGANIC COMPOUNDS
ORGANIC PHOSPHORUS COMPOUNDS
PARASYMPATHOMIMETICS
PHOSPHOLIPIDS
PROTEINS
REACTION KINETICS
RECEPTORS
RODENTS
SOLVOLYSIS
TIME DEPENDENCE
TRITIUM COMPOUNDS
VERTEBRATES