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Vol. 53, Issue 5, 950-962, May 1998
4
2 Nicotinic
Acetylcholine Receptors in M10 Cells: Pharmacological and Spatial
Definition
Department of Biology and Biochemistry, University of Bath, Bath
BA2 7AY, UK
Chronic nicotine up-regulates the number of high affinity nicotinic
acetylcholine receptors (nAChRs) in mammalian brain. Here, we studied
up-regulation of the nAChR composed of 
4 and 
2 subunits in the
M10 cell line by using [3H]epibatidine to measure nAChR
in cells in situ and in membrane preparations. Cultures
were exposed to drugs for 2 days before assay. All agonists
up-regulated [3H]epibatidine binding sites with
EC50 values typically 10-100-fold higher than their
respective Ki values from
competition binding assays. Maximum up-regulation ranged from 40% to
250% above control values. Maximally effective concentrations of the less efficacious agonists methylcarbamylcholine or (±)-epibatidine together with nicotine resulted in less up-regulation than that produced by nicotine alone, showing that they are partial up-regulatory agonists. The antagonists dihydro--erythroidine,
methyllycaconitine, d-tubocurarine, hexamethonium,
decamethonium, and mecamylamine either failed to up-regulate
[3H]epibatidine binding sites or up-regulated mildly at
high concentrations. When tested at non-up-regulating concentrations,
only d-tubocurarine significantly inhibited
agonist-induced up-regulation; this inhibition seemed to be
noncompetitive. Comparison of [3H]epibatidine
displacement in intact M10 cells and membrane preparations by
membrane-impermeant ligands indicated that 85% of
[3H]epibatidine binding sites are intracellular. On
chronic treatment with agonist, the proportion of surface receptors did
not change significantly, indicating that most up-regulated
[3H]epibatidine binding sites are internal. However,
up-regulation is mediated at the cell surface because the impermeant
ligand tetramethylammonium was as efficacious as nicotine in eliciting up-regulation, and methylcarbamylcholine (i.e., impermeant but with low
efficacy) blocked nicotine induced up-regulation. Thus, agonists elicit
up-regulation (mainly of intracellular receptors) by interacting with
cell surface nAChRs that are not compatible with either an active or
high affinity desensitized conformation.
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