Biomedical Engineering Reference
In-Depth Information
Most GPCRs desensitize quickly upon activation via phosphorylation of specii c serine/threonine
residues in the intracellular loops and/or C-terminal by kinases such as G protein-coupled recep-
tor kinases (GRKs). Once phosphorylated,
β
-arrestin molecules will bind to the receptor and cause
arrest of the G protein-mediated signaling and induce internalization. Recent evidence has shown
that
β
-arrestins can activate the tyrosine kinase pathway directly leading to non-G protein mediated
cellular effects (Figure 12.5). In some cases, it has even been possible to develop ligands that selec-
tively activate the
β
-arrestin pathway without activating the G proteins. Such ligands will induce
different cellular effects than ligands activating both signaling pathways.
Recent evidence has shown that some if not all GPCRs exist as dimeric or even oligomeric com-
plexes. As shown in Figure 12.3, family C receptors dimerize via a covalent cystein-bridge, which
leads to either homo- or heterodimers. The latter is, for example, the case for GABA
B
receptors,
which are formed by heterodimerization of GABA
B1
and GABA
B2
receptor subunits whereas, e.g.,
metabotropic glutamate receptors homodimerize. Whether family A and B receptors also homo- or
heterodimerize have been heatedly debated in the literature and only a few examples have been
convincingly shown to be of physiological importance. One such case is in the i eld of opioid recep-
tors (Chapter 19), where it has been shown that the
.
,
μ,
and
δ
subtypes can form pharmacologically
distinct receptor subtypes by heterodimerization.
Collectively, the fact that one GPCR can activate several signaling pathways and heterodimerize
to create additional subtypes has greatly complicated our view of receptor function. From a medici-
nal chemistry point of view it is interesting to note that in some cases it has been possible to develop
ligands selectively targeting a specii c signaling pathway or heterodimer. This has opened up not
only new possibilities but also new challenges in drug design.
7TMR
Agonist
Agonist
P
GRK
P
Gα
β
γ
β
Gα
γ
MAPKs
Tyrosine kinases
AKT
PI3 kinases
NFκB pathway
cAMP
DAG
IP3
2
nd
messengers
Cell response
FIGURE 12.5
The G protein and β-arrestin signaling pathway of 7TM receptors (7TMR). Agonist activa-
tion of 7TMR's initiates the classical G protein cascade (see Figure 12.4 for further details) and rapid receptor
phosphorylation by GRKs. The latter leads to the recruitment of β-arrestins, which causes desensitization and
internalization of the receptor and activation of tyrosine kinase pathways. (Adapted from Lefkowitz, R.J. and
Shenoy, S.K.,
Science
, 308, 512, 2005.)
