Biomedical Engineering Reference
In-Depth Information
12.2.2 L
IGAND
-G
ATED
I
ON
C
HANNEL
R
ECEPTORS
Ligand-gated ion channel receptors can be divided into two major groups, namely, the Cys-loop and
ionotropic glutamate receptor families. The latter family is exclusively excitatory, the former are
either excitatory (serotonin and nicotinic acetylcholine receptors) or inhibitory (glycine and GABA
receptors) by inl ux of Na
+
/Ca
2+
or Cl
−
ions, which will hypo- or hyperpolarize the cell, respectively
(see Chapter 13 for further details).
12.2.2.1 The Cys-Loop Receptor Family
The nicotinic acetylcholine receptor, at the nerve-muscle synapse, is the best understood Cys-loop
receptor, which, upon acetylcholine binding, allow as many as 10,000 potassium and sodium ions per
millisecond to pass through the channel. As shown in Figure 12.6, the receptor consists of two acetyl-
choline binding a
.
1
subunits and three other subunits (
β
1
,
γ
, and
δ
) that form a pentameric pore in the cell
-helices (termed M2), one from each of the i ve receptor
subunits, which have a kink in the middle of the membrane spanning part. This bend is the gate of the
receptor, which in the closed state points toward the channel. Agonist binding to the extracellular part of
the
membrane. The pore itself is lined with i ve
α
-subunits induces local conformational changes that are then relayed through the receptor subunits
and ultimately leads to rotation of the pore-lining
α
-helices and channel opening.
Recently, several high-resolution 3D structures of acetylcholine-binding protein (AChBP), a
water-soluble homolog of the ligand-binding domain of nicotinic acetylcholine receptors from the
snail
Lymnaea stagnalis
, have been solved in the presence of various ligands (Figure 12.6). These
structures have shown that agonists bind in the interface between the subunits and provided detailed
insight into the ligand-receptor interactions. For example, all endogenous agonists of the Cys-loop
family contain an amine, which, according to the AChBP structures, is interacting with a cluster of
aromatic residues via
α
-cation bonding.
Most Cys-loop receptors form heteropentamers (e.g., the neuromuscular nicotinic acetylcholine
receptor described earlier), but some can form homopentamers (e.g., the nicotinic
π
α
7
receptor).
α
γ
E
I
(A)
(B)
FIGURE 12.6
Structure of the family of Cys-loop ligand-gated ion channel receptors. (A) 3D structure of
the neuromuscular nicotinic acetylcholine receptor that consists of i ve subunits (two α-, one β-, one γ-, and
one δ-subunit) forming an ion-channel in the center. An α- and the γ-subunit is shown in red and blue, respec-
tively. The receptor consists of an extracellular (E) ligand-binding domain, a transmembrane domain made
of four α-helices, which is the gate of the receptor, and an intracellular (I) domain. (B) 3D structure of the
acetylcholine-binding protein (AChBP) viewed from the side (left) and top (right). AChBP is a soluble protein
from the snail
Lymnaea stagnalis
, which is homologous to the extracellular ligand-binding domain of the mam-
malian Cys-loop receptors. AChBP consists of i ve identical subunits (one shown in yellow and one in blue),
which forms ligand-binding pockets in their interfaces shown here with nicotine bound (in pink). (Adapted
from Unwin, N.,
J.
Mol. Biol
., 346, 967, 2005; Celie, P.H.N. et al.,
Neuron
, 41, 907, 2004. With permission.)
