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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 8

Module 2: Figure G protein binary switching

Input from cell surface receptors

Guanine nucleotide
exchange factors Signalling responses
GEFs
Cyclic AMP signalling
InsP 3 /DAG signalling
GTP GDP MAP kinase signalling
G G
protein protein PtdIns 3-kinase signalling
GDP GTP PLD signalling
Redox signalling
Cytoskeletal remodelling
GAPs Ion channel modulation
GTPase-activating
Phosphate
factors

Signal transduction through G protein binary switching.
All GTP-binding proteins (G proteins) function through a binary switching mechanism that is driven by the binding of GTP. The G protein is inactive
when bound to GDP. When this GDP is exchanged for GTP, the G protein is activated and can stimulate a number of different signalling responses.
The rapid switching to the active state is facilitated by the guanine nucleotide exchange factors (GEFs) that receive the information coming in from
the receptors on the cell surface. By contrast, the GTPase-activating proteins (GAPs) accelerate the OFF reaction by enhancing the hydrolysis of GTP
to GDP.

GTP-binding proteins elements, and both the Gα subunit and the Gβγ subunit
There are a large number of GTP-binding proteins, which are able to relay information to downstream components
usually are referred to as G proteins, which play a cent- (Module 2: Figure heterotrimeric G protein signalling).
ral role in cell signalling as molecular switches (Module These heterotrimeric G proteins exist in two states.
2: Figure G protein binary switching). These G proteins When the Gα subunit is bound to GDP, it forms a com-
are also GTPases, and the switching is driven by both the plex with Gβγ subunits to form the inactive heterotri-
binding of GTP and its hydrolysis to GDP. The G protein meric complex. When the GPCRs, which are sensitive to a
is inactive when bound to GDP, but when the GDP is ex- wide range of stimuli (Module 1: Figure stimuli for cyclic
changed for GTP, the G protein/GTP complex is active and AMP signalling), are activated, they function as a guan-
transfers information down the signalling pathway until ine nucleotide exchange factor (GEF) to replace the GDP
the endogenous GTPase activity hydrolyses GTP to GDP. with GTP. The binding of GTP not only activates the
The G proteins belong to two groups, the heterotrimeric Gα subunit, but also liberates the Gβγ subunit, both of
Gproteins and the monomeric G proteins, which have which can activate a range of signalling systems. This signal
separate, but overlapping, functions. transduction process is switched off when the endogen-
ous GTPase activity of the Gα subunit hydrolyses GTP
Heterotrimeric G proteins to GDP and the Gα/GDP complex recombines with the
The heterotrimeric G proteins function as transducers for Gβγ subunit to reform the inactive heterotrimeric com-
the G-protein-coupled receptors (GPCRs) that activate a plex. The normal rate of GTPase activity is very low (four
number of cell signalling pathways (Module 1: Table G- to eight conversions per s), which means that the two sub-
protein coupled receptors). These G proteins are made up units have a long time to find their targets. However, there
from 16 Gα,five Gβ and 11 Gγ genes (Module 2: Table are two mechanisms for speeding up the GTPase activity.
heterotrimeric G proteins). These different subunits are Firstly, some of the targets can act to accelerate the GT-
characterized by having various lipid modifications that Pase activity. Secondly, a family of regulators of G protein
serve to insert them into the plasma membrane, where they signalling (RGS) proteins function as GTPase-activating
are positioned to detect information coming in from the proteins (GAPs) that accelerate the Gα subunit GTPase
GPCRs and to relay it to various amplifiers. The Gα sub- activity more than 1000-fold.
units are either palmitoylated or myristoylated near the N- There are G-protein receptor kinases (GRKs) such as
terminus, whereas the Gβγ subunits are prenylated. The β-adrenergic receptor kinase 1 (βARK1), which phos-
heterotrimeric G proteins are extremely versatile signalling phorylate active receptors to provide binding sites for

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