Signal Transduction by G Protein-Coupled Receptors

Introduction
Many vital physiological processes rely on the signal transduction by G protein-coupled
receptors (Table 1). Signal transduction is the process by which a ligand (an extracellular signal
molecule) interacts with a cellular receptor and induces a change in cellular physiology, usually
by an effector (a molecule that brings about a cellular response to a signal) 1. This description
explains the background knowledge on G protein-coupled receptors and G proteins, and the
mechanism of receptor-mediated activation or inhibition of effectors by means of G proteins.

Table 1. Physiological processes governed by G protein-coupled receptors 1.

Ligand Type of G protein- Effector Physiological
coupled receptors Response
Epinephrine β-Adrenergic receptor Adenylyl cyclase Glycogen breakdown
Serotonin Serotonin receptor Adenylyl cylase Behavioral
sensitization
Light Rhodopsin cGMP Visual excitation
phsphodiesterase
IgE-antigen Mast cell IgE receptor Phospholipase C Secretion
complexes
f-Met Peptide Chemotactic receptor Phospholipase C Chemotaxis
Acetylcholine Muscarinic receptor Potassium channel Slowing of pacemaker
activity

G Protein-Coupled Receptors
G protein-coupled receptors (GPCRs) are a vast family of plasma membrane receptors that
contain seven transmembrane α helices (Figure 1) 1. Hundreds of different GPCRs have been
discovered in eukaryotes ranging from yeast to plants and mammals. GPCRs are so named
because they interact with G proteins. In fact, GPCRs translate the binding of ligands into the
activation of G proteins, which ultimately induces respective physiological responses.

Topology of GPCRs
GPCRs usually have the following topology. Their amino (NH2) terminus is located on the
outside of the cell, the seven α helices that pass through the plasma membrane are attached by
polypeptide loops of varying length, and the carboxyl (CO2H) terminus is present on the inside
of the cell (Figure 1) 1. These three distinct regions are often referred to as the extracellular,
transmembrane, and cytosolic domains, respectively. In the extracellular domain, there exist
three loops, which form a ligand-binding site. Similarly, there are also three loops present in the
cytosolic domain, forming a G protein binding site. Both binding sites are critical in the signal
transduction by GPCRs.
 Extracellular Domain

Transmembrane Domain

Cytosolic Domain

Figure 1. A diagram showing the G protein-coupled receptor (left), the G protein (middle), and
the effector (right) 1.

G Proteins
G proteins are also referred as guanine nucleotide-binding proteins because they bind guanine
nucleotides, either as GDP or GTP. Although there are two classes of G proteins (monomers and
heterotrimers), only heterotrimers are associated with GPCRs. G proteins are heterotrimers
because they consist of three different polypeptide subunits: Gα, Gβ, and Gγ 2. G proteins bind to
GPCRs using the Gα subunit at the G protein binding site (Figure 1). In addition, there are two
states of G proteins: active and inactive. The active state consists of Gα subunit binding to GTP
and separated from Gβ and Gγ subunits (often stay together and are referred to as Gβγ subunits).
The inactive state, on the other hand, consists of Gα subunit binding to GDP and attached to Gβ
and Gγ subunits. Because the Gα subunit contains a GTPase (an enzyme that hydrolyzes GTP into
GDP) endogenously, the Gα subunit is capable of inactivating itself.

The Mechanism of GPCRs

The process of receptor-mediated activation or inhibition of effectors by means of G proteins is
explained in eight steps below (Figure 2):
 2. The binding of inactive G protein
to the receptor results in the
exchange of GDP with GTP. The Gα
subunit releases the bound GDP and
binds to GTP, forming a Gα-GTP
complex.

3. The Gα-GTP complex dissociates

from the Gβγ subunits due to low
affinity. The freed complex, then,
moves to bind to a specific effector
and either activates or inhibits it 2.

4. In this instance, the effector,

adenylyl cyclase, is activated by the
binding of Gα-GTP complex to
convert ATP into cAMP 1. The
complex is able to activate or inhibit
the effector as long as it remains
bound and separated from the Gβγ
subunits

1. The ligand binds to the GPCR from the

extracellular domain, and induces a conformational
change in the receptor on the cytosolic domain 2.
The resulting change facilitates the binding of
inactive G protein to the receptor.
Figure 2. A diagram showing steps of signal
transduction by G protein-coupled receptors.1

Figure 2 (Cont.). A diagram showing

steps of signal transduction by G
protein-coupled receptors.1

5. The Gα subunit of the complex possesses an
endogenous GTPase activity that hydrolyzes GTP
into GDP + Pi 2. The hydrolysis typically occurs a
few seconds after the complex is bound to the
effector. Consequently, GTP (bound to the Gα
subunit) is converted to GDP, creating a Gα-GDP
complex.
6. The Gα-GDP complex results in a reduction of
affinity between the effector and the Gα subunit 2.
The complex, thus, dissociates from the effector and
rejoins with the Gβγ subunits. Upon the dissociation,
the activation or inhibition of the effector ends.
7. Steps 2 to 6 can be repeated since the inactive G
protein is reformed and capable of binding to the
ligand-bound receptor again. However, the steps
may be halted by a GRK (G protein-
coupled receptor kinase) to prevent
overstimulation 1. The receptor on
the cytosolic domain is
phosphorylated by the GRK.
8. The phosphorylated receptor is
bound to an arrestin (a molecule that
competes for binding with the G
protein), which inhibits the GPCR
from activating additional G
proteins. After a certain period of
time, the receptor bound to arrestin
will be taken up by endocytosis (a
mechanism for the uptake of fluid
and solutes into a cell) and replaced
with a fresh GPCR to restart the
whole process all over again 1.

Summary
Signal transduction by G protein-coupled receptors is initiated when the ligand binds to the
receptor, altering its conformation and increasing its affinity for the G protein to which it binds.
The Gα subunit bound to the GPCR exchanges its GDP with GTP. As a result, the Gα subunit
dissociates from the Gβγ subunits and binds to an effector, activating or inhibiting the effector.
The activated or inhibited effector produces a respective physiological response. The GTPase
activity of the Gα subunit hydrolyzes the bound GTP after a few seconds of binding to the
effector, deactivating the Gα subunit. The Gα subunit with GDP reassociates with the Gβγ
subunits, ceasing the activity of the effector. The inactive G protein is now reformed and can
bind to the receptor again. To avoid overstimulation, however, the receptor is phosphorylated by
the GRK and bound by the arrestin, inhibiting additional G proteins from activating. The
arrestin-bound receptor is removed after a specific period by endocytosis and replaced with a
new GPCR to initiate the whole process all over again.

Works Cited
1. Karp G. Cell and Molecular Biology: Concepts and Experiments, 4th ed. Von Hoffmann
Press: John Wiley & Sons, Inc; 2005.
2. Compton R. Intracellular Signaling In: BSCI230 Lecture; College Park, MD; 2006 Nov.
p. 36-39.