Drug-Receptor Interaction VIII

Mode of Operation of G-Protein-
Coupled Receptors
Signal transduction at G-protein-coupled
receptors uses essentially the same
basic mechanisms . Agonist binding
to the receptor leads to a change in receptor
protein conformation. This
change propagates to the G-protein: the
!-subunit exchanges GDP for GTP, then
dissociates from the two other subunits,
associates with an effector protein, and
alters its functional state. The !-subunit
slowly hydrolyzes bound GTP to GDP.
G!-GDP has no affinity for the effector
protein and reassociates with the " and
subunits . G-proteins can undergo
lateral diffusion in the membrane; they
are not assigned to individual receptor
proteins. However, a relation exists
between receptor types and G-protein
types . Furthermore, the !-subunits
of individual G-proteins are distinct in
terms of their affinity for different effector
proteins, as well as the kind of influence
exerted on the effector protein. G-
GTP of the GS-protein stimulates adenylate
cyclase, whereas G-GTP of the Giprotein
is inhibitory. The G-proteincoupled
receptor family includes muscarinic
cholinoceptors, adrenoceptors
for norepinephrine and epinephrine, receptors
for dopamine, histamine, serotonin,
glutamate, GABA, morphine, prostaglandins,
leukotrienes, and many other
mediators and hormones.
Major effector proteins for G-protein-
coupled receptors include adenylate
cyclase (ATP ! intracellular messenger
cAMP), phospholipase C (phosphatidylinositol
intracellular messengers
inositol trisphosphate and diacylglycerol),
as well as ion channel
proteins. Numerous cell functions are
regulated by cellular cAMP concentration,
because cAMP enhances activity of
protein kinase A, which catalyzes the
transfer of phosphate groups onto functional
proteins. Elevation of cAMP levels
inter alia leads to relaxation of smooth
muscle tonus and enhanced contractility
of cardiac muscle, as well as increased
glycogenolysis and lipolysis .
Phosphorylation of cardiac calcium-
channel proteins increases the
probability of channel opening during
membrane depolarization. It should be
noted that cAMP is inactivated by phosphodiesterase.
Inhibitors of this enzyme
elevate intracellular cAMP concentration
and elicit effects resembling those
of epinephrine.
The receptor protein itself may
undergo phosphorylation, with a resultant
loss of its ability to activate the associated
G-protein. This is one of the
mechanisms that contributes to a decrease
in sensitivity of a cell during prolonged
receptor stimulation by an agonist
(desensitization).
Activation of phospholipase C leads
to cleavage of the membrane phospholipid
phosphatidylinositol-4,5 bisphosphate
into inositol trisphosphate (IP3)
and diacylglycerol (DAG). IP3 promotes
release of Ca2+ from storage organelles,
whereby contraction of smooth muscle
cells, breakdown of glycogen, or exocytosis
may be initiated. Diacylglycerol
stimulates protein kinase C, which
phosphorylates certain serine- or threonine-
containing enzymes.
The subunit of some G-proteins
may induce opening of a channel protein.
In this manner, K+ channels can be
activated (e.g., ACh effect on sinus node,
; opioid action on neural impulse
transmission).