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Vol. 56, Issue 6, 1245-1253, December 1999
Departments of Psychiatry and Pharmacology, The Pennsylvania State
University College of Medicine, Hershey, Pennsylvania
Gallamine allosterically modulates the binding of classical muscarinic
ligands with a potency order of M2 > M1,M4 > M3,M5. We
have suggested previously that the M2/M5 and
M2/M3 selectivities are attributable to an
epitope in the sixth transmembrane region or third outer loop (o3)
region of the receptor. In this study, analysis of numerous point
mutations in this region of the M5 receptor found that a
mutation of V 
N resulted in an increased affinity toward gallamine,
suggesting that the asparagine residue at M2419
is responsible for gallamine's M2/M5
selectivity. Mutations in the other subtypes indicated that the acidic
residues found at this position in M1 and M4
are associated with slightly higher affinity toward gallamine, whereas
the valine and lysine residues of M5 and M3,
respectively, are associated with significantly lower affinity. In the
o2 region, replacement of an acidic sequence of M2
(EDGE) by the corresponding neutral sequence of M1
(LAGQ) reduced the affinity toward gallamine, as reported previously by
others; the converse substitution of the acidic sequence into M1 significantly increased affinity for gallamine.
Substitution of the M1 sequence into this region of
M5 markedly reduced affinity toward gallamine, whereas
substitution into M4 had no effect. All of the above
mutations are consistent with gallamine binding with a similar
orientation at each subtype, such that it interacts with acidic
residues in the o2 region of M3 and M5 and with
acidic residues in the o3 region of M1 and M4;
gallamine appears to interact with both regions of the M2 subtype.
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