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Mode of Operation of G-Protein coupled


Receptors

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Signal transduction at G-protein coupled receptors uses essentially the same basic
mechanism (A). Agonist binding to the receptor leads to a change in receptor protein
conformation. This change propagates to the G-protein: the α-subunit exchanges GDP for
GTP, then dissociates from the two other subunits, associates with an effector protein and
alters its functional state. In principle, the β- and γ-subunits are also able to interact with
effector proteins. The α-subunit slowly hydrolyses bound GTP to GDP. Gα-GDP has no
af nity for the effector protein and reassociates with the β- and γ-subunits (A). Gproteins
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
(B). Furthermore, the α-subunits of individual G-proteins are distinct in terms of their af
nity for different effector proteins, as well as the kind of influence exerted on the effector
protein. Gα-GTP of the Gs-protein stimulates adenylate cyclase, while Gα- GTP of the
Gi -protein is inhibitory. The G-protein-coupled receptor family includes muscarinic
cholinoceptors, adrenoceptors for norepinephrine and epinephrine, as well as receptors
for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins,
leukotrienes, and many other mediators and hormones.

Major effector proteins for G-proteincoupled receptors include adenylate cyclase (ATP
† intracellular messenger cAMP), phospholipase C (phosphatidylinositol † intracellular
messengers inositol trisphosphate and diacylglycerol) as well as ion channel proteins
(B). 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 leads interalia to relaxation
of smooth muscle tonus, enhanced contractility of cardiac muscle, as well as increased
glycogenolysis and lipolysis (p. 88). 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 contribute
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 phospholipids


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. DAG
stimulates protein kinase C, which phosphorylates certain serine- or threonine- containing
enzymes.

Certain G-proteins can induce opening of channel proteins. In this way, potassium
channels can be activated (e. g., acetylcholine effect on sinus node, p.104; opioid effect
on neural impulse transmission,).

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