Biomedical Engineering Reference
In-Depth Information
Numerous subunits for both nicotinic acetylcholine receptors and GABA
A
receptors have been
cloned, which can theoretically heteromerize to a staggering high number of subunit combinations.
However, in reality, only certain subunit combinations are present and even fewer combinations
have therapeutic interest. The glycine and serotonin Cys-loop receptors have fewer subunits, which
each can form homo- and heterodimers. Interestingly, some subunits are unable to form their part
of the agonist binding pocket in either one or both sides of the two interfaces they participate in.
Depending on their subunit composition, Cys-loop receptors can bind from two to i ve agonist
molecules. For example, the neuromuscular nicotinic acetylcholine receptor binds two agonist mol-
ecules whereas the nicotinic
α
7
receptor and AChBP can bind i ve agonist molecules (Figure 12.6).
Whether all agonist binding sites need to be occupied in order to achieve receptor activation has yet
to be demonstrated.
12.2.2.2 The Ionotropic Glutamate Receptor Family
The ionotropic glutamate receptor family comprise of the 15 NMDA, AMPA, and kainic acid
receptors listed in Figure 12.1 and two orphan receptors (termed
1-2) with unknown function. The
name of the receptor family is a bit misleading as NR1 and NR3A-B actually has glycine as ligand
(Chapter 15). Nevertheless, all 17 receptor subunits have the same overall structure: two large extra-
cellular domains referred to as the N-terminal domain (NTD) and agonist-binding domain (ABD),
a transmembrane domain (TMD) consisting of three transmembrane segments and a reentry loop
and a C-terminal domain (CTD) (Figure 12.7). It is quite interesting to note the resemblance of
the structures of the TMD with the amino-terminal domain of potassium channels (Chapter 13),
respectively. Functional receptors are comprised of four subunits assembled around the ion channel.
All NMDA receptors are heteromeric assemblies as NR1 together with either NR2 or NR3 subunits
(forming glutamate or glycine receptors, respectively) whereas AMPA and kainic acid receptors can
either be homo- or heteromeric assemblies.
δ
NTD
N
ABD
TMD
CTD
c
mGluR1
GluR2
(A)
(B)
FIGURE 12.7
(A) Illustration of a single ionotropic glutamate receptor subunit with the location of the
N-terminal domain (NTD), agonist-binding domain (ABD), transmembrane domain (TMD), and C-terminal
domain (CTD) noted. The colored ABD with glutamate in the binding site is based on the crystal structure
obtained of the soluble GluR2 binding core shown in (B). (Adapted from Bräuner-Osborne, H. et al.,
J.
Med.
Chem
., 43, 2610, 2000.) (B) Structure of the ABD of GluR2 in the open inactive form (left) and the closed
active form with glutamate bound in the cleft (right). The difference in conformation of glutamate bound to
mGluR1 and GluR2 are also shown. The structures were generated using the program “Swiss PDB viewer 3.5”
with coordinates from Brookhaven Protein Data Base.
