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áková,ek
Institute of Physiology, Academy of Sciences of the Czech Republic,
14220 Prague, Czech Republic (J.J., L.B., S.T.), and
Neuroscience
Research in Psychiatry, University of Minnesota Medical School,
Minneapolis, Minnesota 55455 (E.E.E.)
It is well known that allosteric modulators of muscarinic
acetylcholine receptors can both diminish and increase the affinity of
receptors for their antagonists. We investigated whether the allosteric
modulators can also increase the affinity of receptors for their
agonists. Twelve agonists and five allosteric modulators were tested in
experiments on membranes of CHO cells that had been stably transfected
with genes for the M1-M4 receptor subtypes. Allosterically induced changes in the affinities for agonists were
computed from changes in the ability of a fixed concentration of each
agonist to compete with
[3H]N-methylscopolamine for the binding to
the receptors in the absence and the presence of varying concentrations
of allosteric modulators. The effects of allosteric modulators varied
greatly depending on the agonists and the subtypes of receptors. The
affinity for acetylcholine was augmented by (
)-eburnamonine on the
M2 and M4 receptors and by brucine on the
M1 and M3 receptors. Brucine also enhanced the
affinities for carbachol, bethanechol, furmethide, methylfurmethide,
pilocarpine,
3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (pentylthio-TZTP), oxotremorine-M, and McN-A-343 on the M1,
M3, and M4 receptors, for pentylthio-TZTP on
the M2 receptors, and for arecoline on the M3
receptors. ()-Eburnamonine enhanced the affinities for carbachol,
bethanechol, furmethide, methylfurmethide, pentylthio-TZTP,
pilocarpine, oxotremorine and oxotremorine-M on the M2
receptors and for pilocarpine on the M4 receptors.
Vincamine, strychnine, and alcuronium displayed fewer positive
allosteric interactions with the agonists, but each allosteric
modulator displayed positive cooperativity with at least one agonist on at least one muscarinic receptor subtype. The highest degrees of
positive cooperativity were observed between ()-eburnamonine and
pilocarpine and ()-eburnamonine and oxotremorine-M on the M2 receptors (25- and 7-fold increases in affinity,
respectively) and between brucine and pentylthio-TZTP on the
M2 and brucine and carbachol on the M1
receptors (8-fold increases in affinity). The discovery that it is
possible to increase the affinity of muscarinic receptors for their
agonists by allosteric modulators offers a new way to subtype-specific
pharmacological enhancement of transmission at cholinergic (muscarinic)
synapses.
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