Biomedical Engineering Reference
In-Depth Information
Fig. 3 A diagrammatic model of ligand-gated ion channels. These channels are pentameric
proteins, in which each subunit has a large extracellular domain at the N-end, four transmembrane
(TM) segments, and an intracellular (TM3-TM4) loop. Reprinted with permission from [
9
].
Copyright 2002 the American Physiological Society
interacellular (TM3-TM4) loop (Fig.
3
)[
9
]. GABA and glycine receptors respond
to the inhibitory neurotransmitters by opening a chloride-selective central pore
lined with five TM2 segments. The central pore of LGICs is the only functional
domain for which structure-function relationships are relatively well understood
due to numerous electrophysiological, pharmacological, mutagenesis, and molecu-
lar modeling studies [
83
]. There is a consensus that five TM2 segments, predomi-
nantly in the
-helical conformations, contribute to the structure of this central pore
[
84
-
86
]. In a drug-receptor binding study with GABA and glycine receptors,
Zhorov and Bregestovski [
83
] found that the binding of the compounds such
as cyanotriphenylborate (CTB) and picrotoxin (PTX) in the cytoplasmic half of
the pore is stabilized by van der Waals interactions with five TM2 segments. A few
more observations made by these authors in this study provided the support to
general pore structure of LGICs as discussed.
Although both GABA and glycine receptors are ligand-gated Cl
channels, they
widely differ in their molecular structures, expressions, functional properties, and
disruption effects.
a
2.4.1 Molecular Structures
Out of the three different types of GABA receptors (GABA
A,
GABA
B
, and
GABA
C
), only GABA
A
and GABA
C
receptors act as Cl
channels [
87
,
88
] and
GABA
B
receptors are G-protein-coupled receptors [
89
]. However, as Cl
channels
GABA
A
receptors have been most widely discussed. These GABA receptors are
