Biology Reference
In-Depth Information
topographical organization with seven transmembrane spanning
a
-helices
connected by three intracellular and three extracellular loops with extracel-
lular amino and intracellular carboxyl termini. GPCRs transduce the infor-
mation provided by a multitude of physical and chemical extracellular
stimuli into intracellular second messengers and thereby have the ability
to mediate and modulate essential biological functions. However, besides
their numerous important roles in basic cellular physiology, dysregulation
of GPCR function eventually results in pathophysiologic conditions. As a
consequence, understanding the molecular mechanisms underlying GPCR
function is fundamental to the development of new drugs for a host of
human diseases.
The classical paradigm for transduction of external signals across the
plasma membrane into the cell following ligand binding to GPCRs involves
the coupling of GPCRs to heterotrimeric guanine nucleotide-binding pro-
teins (G proteins), which promotes the exchange of GDP for GTP on the
G protein
a
subunit. This, in turn, leads to the dissociation of G
a
and G
bg
subunits.
1
The activated subunits subsequently regulate the activity of a
wide variety of effectors, thus regulating intracellular second messenger
levels that mediate the cellular response to receptor activation. Besides
the G protein-dependent activation of downstream effectors such as ion
channels, phospholipases, and adenylyl cyclases, agonist-mediated GPCR
activation also results in multiple molecular protein interactions that initiate
(1) receptor desensitization, (2) receptor endocytosis, (3) intracellular traf-
ficking between intracellular vesicular compartments, (4) the activation of
G protein-independent signaling pathways, and (5) either receptor res-
ensitization or downregulation.
2
These cellular processes display remarkable kinetic differences. Whereas
desensitization occurs within seconds, endocytosis takes place over minutes
and resensitization ensues within minutes to hours.
3
All of these processes are
governed by a myriad of intracellular accessory proteins, generally termed
GPCR-interacting proteins (GIPs). Within the last two decades of research,
the list of GIPs has expanded rapidly and continues to grow.
4-8
Notably, one
of the first GIPs identified is the cytosolic protein arrestin, which was first
shown to bind to GRK1-phosphorylated rhodopsin.
9
The arrestin family
in vertebrates is now known to consist of four members: two visual arrestins,
arrestin-1 and arrestin-4, that are limited in their expression to the photo-
transduction pathway (retinal rods and cones), and the two nonvisual
arrestins,
b
-arrestin-1 and
b
-arrestin-2 (alternatively known as arrestin-2
and arrestin-3).
b
-Arrestin-1 and
b
-arrestin-2 are ubiquitously expressed
Search WWH ::
Custom Search