Age-related changes in pulmonary muscarinic receptor binding properties
Wills-Karp, M.
American Journal of Physiology 265(2 Pt 1): L103-L109
1993
ISSN/ISBN: 0002-9513 PMID: 8368321 Document Number: 419746
The goal of this study was to elucidate mechanisms responsible for age-related reductions in responsiveness to cholinergic muscarinic stimulation in guinea pigs, by examining the binding properties of muscarinic receptors and their coupling to guanine nucleotide regulatory proteins as a function of animal age. In addition, the binding constants of three selective muscarinic receptor antagonists pirenzepine, (11-((2-((diethylamino)methyl)-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyrido(2,3)(1,4)benzodiazepine-6-on), and 4-diphenylacetoxy-N-methylpiperidine methobromide were examined. We found that there were no changes in either the receptor density or the affinity of the muscarinic receptor with age. There was a significant reduction in the affinity constant for the high-affinity agonist binding site in the old tissues (7.63 +- 0.08) compared with the young tissues (8.31 +- 0.10). Guanine nucleotides lowered agonist affinity for the receptor in young lungs, however, they had no effect on agonist binding in old tissues. Antagonist competition binding curves in young tissues revealed that 73% of the receptors are of the M-2 type, with 27% being of the M-3 subtype. In contrast, antagonist competition binding curves in the old tissues revealed that 37% of the receptors were of the M-2 subtype, 30% were M-3, and 33% were of the M-1 subtype. Our studies provide evidence that the loss of sensitivity to cholinergic muscarinic stimulation in the senescent lung may be due to changes in both muscarinic receptor subtypes and receptor coupling to G proteins.