G-protein-Coupled Receptors
G-protein-Coupled Receptors
G-protein-Coupled Receptors
s
G Protein Signal Cascade
Most signal molecules targeted to a cell bind at the cell sur
face to receptors embedded in the plasma membrane.
Only signal molecules able to cross t
he plasma membrane (e.g., steroid h
ormones) interact with intracellular r
eceptors.
A large family of cell surface recept
ors have a common structural motif,
7 transmembrane a-helices.
Rhodopsin was the 1st member of th
is family to have its 7-helix structur
e confirmed by X-ray crystallograph
y. R h o d o p s in PD B 1F88
Rhodopsin is unique in that it se
nses light.
Most 7-helix receptors have do
mains facing the extracellular sid
e of the plasma membrane that re
cognize & bind particular signal
molecules (ligands).
R h o d o p s in PD B 1F88
The signal is passed from a 7-helix recept
or to an intracellular G-protein.
Seven-helix receptors are thus called GPCR, or
G-Protein-Coupled Receptors.
Approx. 800 different GPCRs are encoded in the hu
man genome.
G-protein-Coupled Receptors may dimerize or form oli
gomeric complexes within the membrane.
Ligand binding may promote oligomerization, which ma
y in turn affect activity of the receptor.
Various GPCR-interacting proteins (GIPs) modulate rec
eptor function. Effects of GIPs may include:
altered ligand affinity
receptor dimerization or oligomerization
control of receptor localization, including transfer to o
r removal from the plasma membrane
promoting close association with other signal proteins
G-proteins are heterotrimeric, with 3 subunits a, b, g.
A G-protein that activates cyclic-AMP formation withi
n a cell is called a stimulatory G-protein, designated
Gs with alpha subunit Gsa.
Gs is activated, e.g., by receptors for the hormones epin
ephrine and glucagon.
The b-adrenergic receptor is the GPCR for epinephri
ne.
hormone
signal
outside
GPCR plasma
The a subunit of membrane
outside
GPCR plasma
The complex o membrane
f b & g subunit
agga cytosol
s Gb,g inhibits AC
GDP bbGTP
Ga.
GTP GDP ATP cAMP + PPi
outside
GPCR plasma
membrane
agga cytosol
AC
GDP bbGTP
outside
GPCR plasma
membrane
agga cytosol
AC
GDP bbGTP
outside
GPCR plasma
membrane
agga cytosol
AC
GDP bbGTP
GDP
GEF GAP
GTP Pi
protein-GDP (inactive)
GDP
GEF GAP
GEFs, Guanine Nucleoti GTP Pi
de Exchange Factors, pr
omote GDP/GTP excha protein-GDP (inactive)
nge.
An activated receptor (GPCR) normally serves a
s GEF for a heterotrimeric G-protein.
Alternatively, AGS (Activator of G-protein Signalin
g) proteins may activate some heterotrimeric G-pr
oteins, independent of a receptor.
Some AGS proteins have GEF activity.
Phosphatidylinositol Signal Cascad
es
O
O H2C O C R2
R1 C O CH O
H2C O P O
O- H
1 6
OH OH
H OH
2 H 5
OH
phosphatidyl- H H
3 4
inositol H OH
O H2C O C R2
R1 C O CH O
H2C O P O
O- H
1 6
OH OPO32-
H OH
2 OH H 5
H H
PIP2 3 4
phosphatidylinositol- H OPO32-
4,5-bisphosphate
++
endoplasmic
View an ani Ca reticulum
mation.
Ca++-ATPase
ATP ++ ADP + Pi
Ca