The nicotinic acetylcholine receptor (nAChR) is a cation-selective ion
channel that opens in response to acetylcholine binding. The related
glycine receptor (GlyR) is anion selective. The pore-lining domain of
each protein may be modeled as a bundle of five parallel M2 helices. M
odels of the pore-lining domains of homopentameric nAChR and GlyR have
been used in continuum electrostatics calculations to probe the origi
ns of ion selectivity. Calculated pK(A), values suggest that ''rings''
of acidic or basic side chains at the mouths of the nAChR or GlyR M2
helix bundles, respectively, may not be fully ionized. In particular,
for the nAChR the ring of glutamate side chains at the extracellular m
outh of the pore is predicted to be largely protonated at neutral pH,
whereas those glutamate side chains in the intracellular and intermedi
ate rings (at the opposite mouth of the pore) are predicted to be full
y ionized. Inclusion of the other domains of each protein represented
as an irregular cylindrical tube in which the M2 bundles are embedded
suggests that both the M2 helices and the extramembrane domains play s
ignificant roles in determining ion selectivity.