Biomedical Engineering Reference
In-Depth Information
Recently, high-resolution 3D structures of the isolated ABD of the ionotropic glutamate receptor
subunits NR1, NR2A, GluR2, GluR5, and GluR6 have been determined in the absence of ligands
and with full and partial agonists, antagonists, and allosteric modulators. Overall these studies have
shown that activation is initiated by closure of the ABD around the ligand, which is then relayed to
the membrane spanning part of the receptor causing an opening of the channel pore (Figure 12.7).
The plentitude of ABD structures has also provided a compelling insight into ligand-receptor inter-
actions and has, for example, shown that the conformation of glutamate bound to various glutamate
receptors is quite different as illustrated in Figure 12.7. Such information is very valuable in the
design of glutamate receptor subtype selective compounds as will be discussed in further detail in
Chapter 15.
12.2.3 T
YROSINE
K
INASE
R
ECEPTORS
As illustrated (refer to Figure 12.9) the tyrosine kinase receptors have a large extracellular agonist-
binding domain, one transmembrane segment and an intracellular domain. The receptors can be
divided into two groups: those that contain the tyrosine kinase as an integral part of the intracellular
domain and those that are associated with a Janus kinase (JAK). Examples of the former group are
the insulin receptor family and the epidermal growth factor (EGF) receptor family and examples of
the latter are the cytokine receptor family such as the erythropoietin (EPO) receptor and the throm-
bopoietin (TPO) receptor. However, both groups share the same overall mechanism of activation:
upon agonist binding two intracellular kinases are brought together, which will initiate autophos-
phorylation of tyrosine residues of the intracellular tyrosine kinase domain (Figure 12.8). This will
attract other proteins (e.g., Shc/Grb2/SOS and STAT for the two receptor groups, respectively) that
are also phosphorylated and this will initiate protein cascades and ultimately lead to regulation of
transcriptional factors (e.g., Elk-1, Figure 12.8) and thus regulation of genes involved in, e.g., cell
proliferation and differentiation. As described for the GPCRs, all the proteins in the intracellular
activation cascades are heterogeneous leading to individual responses (i.e., regulation of different
subset of genes) in individual cell types.
Agonist
Cell membrane
P
P
Shc
Grb2/SOS
Ras
Raf
MEK
MAPK
MAPK
ElK-1
Gene expression
FIGURE 12.8
Cartoon of a protein cascade initiated by agonist binding to two tyrosine kinase receptors
(TKR) causing autophosphorylation of the dimerized intracellular receptor domains. This causes activation of
a cascade of intracellular proteins (abbreviated Shc, Grb2/SOS, Ras, Raf, MEK, and MAPK), which ultimately
leads to activation of transcription factors (e.g., Elk-1) and thus regulation of gene expression.
