DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

54
A. Activation by Ligand Binding of GPCR
Basal
L
Active
L
SECTION I
GENERAL PRINCIPLES
α
GDP
β
γ
GDP
Ligand binding stimulates
GDP release; GTP binds to α
PO 4
RGS
GTP
Active α-GTP returns to basal state,
by RGS proteins
α
GTP
β
γ
Modulation
of effectors
B. Modulation of Effectors
by βγ
by phosphorylation
and scaffold proteins
L
by α-GTP
Effector
γ
β
β
γ
—PO 4
α
GTP
Effector
PI3 K
K + channel
Ca 2+ channel
GRKs
Arrestin
AC (G s )
AC (G i )
PLC (G q )
Figure 3–8. Diagram showing the stimulation of a G–protein coupled receptor by ligand, the activation of the G protein, and stimulation
of selected effectors. Schematic diagram of the mechanisms involved in the control of cell function by G–protein coupled receptors,
G proteins, and effectors. In the absence of ligand, the receptor and G protein heterotrimer form a complex in the membrane with
the Gα subunit bound to GDP. Following binding of ligand, the receptor and G protein α subunit undergo a conformational change
leading to release of GDP, binding of GTP, and dissociation of the complex. The activated GTP-bound Gα subunit and the freed βγ
dimer bind to and regulate effectors. The system is returned to the basal state by hydrolysis of the GTP on the α subunit; a reaction
that is markedly enhanced by the RGS proteins. Prolonged stimulation of the receptor can lead to down-regulation of the receptor.
This event is initiated by G protein receptor kinases (GRKs) that phosphorylate the C terminal tail of the receptor, leading to recruitment
of proteins termed arrestins; arrestins bind to the receptor on the internal surface, displacing G proteins and inhibiting signaling.
Detailed descriptions of these signaling pathways are given throughout the text in relation to the therapeutic actions of drugs
affecting these pathways.
patterns of selectivity among agonist or antagonist ligands.
When selective ligands are not known, the receptors
are more commonly referred to as isoforms rather
than as subtypes. The distinction between classes and
subtypes of receptors, however, is often arbitrary or historical.
The α 1
, α 2
, and β adrenergic receptors differ
from each other both in ligand selectivity and in coupling
to G proteins (G q
, G i
, and G s
, respectively), yet α and
β are considered receptor classes and α 1
and α 2
are considered
subtypes. The α 1A
, α 1B
, and α 1C
receptor isoforms
differ little in their biochemical properties,
although their tissue distributions are distinct. The β 1
,
β 2
, and β 3
adrenergic receptor subtypes exhibit differences
in both tissue distribution and regulation by