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Vol. 53, Issue 4, 759-765, April 1998
Department of Pharmacology (P.G.S, J.A.K., J.M.E.) and
Glaxo
Institute of Applied Pharmacology (J.A.K.), University of Cambridge,
Cambridge, CB2 1QJ, United Kingdom
The molecular mechanisms underlying the internalization of G
protein-coupled receptors are still poorly understood. Normally agonists but not antagonists cause internalization (defined here as a
reduction in the number of receptors at the cell surface), suggesting a
functional relationship between agonist activity and internalization.
In this study we investigated the effects of eight muscarinic ligands
on the rate constants for endocytosis and recycling of m3 muscarinic
acetylcholine receptors in human SH-SY5Y neuroblastoma cells. We found
that there was a linear correlation between the intrinsic activity of
the ligand and its ability to increase the rate constant for
endocytosis, suggesting that the same active conformation of the
receptor is responsible for stimulating both second messenger
generation and receptor endocytosis. In contrast, the rate constant for
recycling did not depend on which agonist had triggered receptor
endocytosis, suggesting that recycling is a purely constitutive
process. Because receptor internalization depends on the rate constants
for both endocytosis and recycling, the relationship between
internalization and intrinsic activity is nonlinear. In particular,
mathematical modeling of receptor trafficking revealed that under
certain conditions very small (3% or less) increases in the rate
constant for endocytosis are sufficient to cause substantial receptor
internalization. An important implication of this analysis is that
extremely weak partial agonists (which may in practice be
indistinguishable from antagonists) may produce significant receptor
internalization.
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