Jp. Kukkonen et al., PSEUDO-NONCOMPETITIVE ANTAGONISM OF M-1, M-3, AND M-5, MUSCARINIC RECEPTOR-MEDIATED CA2- MOBILIZATION BY MUSCARINIC ANTAGONISTS, Biochemical and biophysical research communications, 243(1), 1998, pp. 41-46
Muscarinic receptors M-1, M-3 and M-5 were expressed in Sf9 cells, Thr
ee different patterns of inhibition of Ca2+ elevations could be resolv
ed for the subtype non-selective muscarinic receptor antagonists: (i)
a right shift of the agonist dose-response curve, (ii) a right shift o
f the agonist dose-response curve and a depression of the maximum sign
al, and (iii) an intermediate pattern where the antagonist apparently
behaved more competitively at higher concentrations, A simulation perf
ormed assuming that these differences are due to differences in the di
ssociation rates of the antagonists reproduced all three different mod
es of inhibition; the novel intermediate pattern (iii) is suggested to
be caused by an intermediate antagonist dissociation rate, A direct c
orrelation between the type of inhibition and the measured dissociatio
n rate of the antagonists was also observed, Functional selectivity be
tween receptor subtypes based on the dissociation constants is suggest
ed based on the results, (C) 1998 Academic Press.