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The Journal of Neuroscience, December 1, 2002, 22(23):10172-10181
Changes in Conformation and Subcellular Distribution of  4 2
Nicotinic Acetylcholine Receptors Revealed by Chronic Nicotine
Treatment and Expression of Subunit Chimeras
Patricia C.
Harkness and
Neil S.
Millar
Department of Pharmacology, University College London, London, WC1E
6BT, United Kingdom
Chronic exposure to nicotine, as occurs during tobacco smoking, is
one of several factors that have been reported to cause an upregulation
of neuronal nicotinic acetylcholine receptors (nAChRs). Here, the
influence of both chronic exposure to nicotine (10 µM, 24 hr) and the coexpression of subunit chimeras has been examined in
cultured cell lines expressing recombinant  4 2 nAChRs, a major
nicotinic receptor subtype expressed in the mammalian brain. Evidence
is presented which demonstrates that both chronic exposure to nicotine
and the coexpression of subunit chimeras upregulates levels of receptor
expressed on the cell surface. Immunoblotting data indicate that
neither chronic nicotine treatment nor coexpressed subunit partners
greatly affect the level of total subunit protein. This finding,
together with radioligand and antibody binding studies conducted on
both intact and permeabilized cells, reveals that receptor upregulation
corresponds to an increase in the proportion of total receptor
expressed on the cell surface. It is also apparent that
nicotine-induced nAChR upregulation is very strongly dependent on
subunit composition and subunit domains. An important aspect of this
study is that direct evidence has been obtained indicating that both
chronic exposure to nicotine and coexpressed subunit partners can
influence subunit conformation. The influence of chronic nicotine
treatment on subunit folding may help to explain the phenomenon of
nicotine-induced receptor upregulation. The finding that subunit
conformation can be influenced by coassembled subunit partners is in
agreement with models of receptor assembly which propose that subunit
folding continues after initial subunit-subunit interactions.
Key words:
nicotinic; acetylcholine receptor; folding; conformation; assembly; chimera
Copyright © 2002 Society for Neuroscience 0270-6474/02/222310172-10$05.00/0
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