G proteins, also known as guanine nucleotide-binding proteins, are a
family of proteins that act as molecular switches inside cells, and are involved
in transmitting signals from a variety of stimuli outside a cell to its
interior. Their activity is regulated by factors that control their ability to
bind to and hydrolyze guanosine triphosphate to guanosine diphosphate.
When they are bound to GTP, they are 'on', and, when they are bound to GDP,
they are 'off'. G proteins belong to the larger group of enzymes called GTPases.
There are two classes of G proteins. The first function as monomeric small
GTPases, while the second form and function as heterotrimeric G protein
complexes. The latter class of complexes is made up of alpha, beta and gamma
subunits. In addition, the beta and gamma subunits can form a stable dimeric
complex referred to as the beta-gamma complex.
G proteins located within the cell are activated by G protein-coupled receptors
that span the cell membrane. Signaling molecules bind to a domain of the GPCR
located outside the cell, and an intracellular GPCR domain then in turn
activates a particular G protein. Some inactive-state GPCRs have also been
shown to be "pre-coupled" with G proteins. The G protein activates a
cascade of further signaling events that finally results in a change in cell
function. G protein-coupled receptor and G proteins working together transmit
signals from many hormones, neurotransmitters, and other signaling
factors. G proteins regulate metabolic enzymes, ion channels, transporter, and
other parts of the cell machinery, controlling transcription, motility,
contractility, and secretion, which in turn regulate diverse systemic functions
such as embryonic development, learning and memory, and homeostasis.
History G proteins were discovered when Alfred
G. Gilman and Martin Rodbell investigated stimulation of cells by
adrenaline. They found that when adrenaline binds to a receptor, the
receptor does not stimulate enzymes directly. Instead, the receptor
stimulates a G protein, which then stimulates an enzyme. An example is
adenylate cyclase, which produces the second messenger cyclic AMP. For this
discovery, they won the 1994 Nobel Prize in Physiology or Medicine.
Nobel prizes have been awarded for many aspects of signaling by G proteins and
GPCRs. These include receptor antagonists, neurotransmitters,
neurotransmitter reuptake, G protein-coupled receptors, G proteins,
second messengers, the enzymes that trigger protein phosphorylation in
response to cAMP, and consequent metabolic processes such as
glycogenolysis. Prominent examples include:
The 1947 Nobel Prize in Physiology or Medicine to Carl Cori, Gerty Cori and
Bernardo Houssay, for their discovery of how glycogen is broken down to glucose
and resynthesized in the body, for use as a store and source of energy.
Glycogenolysis is stimulated by numerous hormones and neurotransmitters including
adrenaline. The 1970 Nobel Prize in Physiology or
Medicine to Julius Axelrod, Bernard Katz and Ulf von Euler for their work on the
release and reuptake of neurotransmitters.
The 1971 Nobel Prize in Physiology or Medicine to Earl Sutherland for
discovering the key role of adenylate cyclase, which produces the second
messenger cyclic AMP. The 1988 Nobel Prize in Physiology or
Medicine to George H. Hitchings, Sir James Black and Gertrude Elion "for
their discoveries of important principles for drug treatment" targeting
GPCRs. The 1992 Nobel Prize in Physiology or
Medicine to Edwin G. Krebs and Edmond H. Fischer for describing how reversible
phosphorylation works as a switch to activate proteins, and to regulate
various cellular processes including glycogenolysis.
The 1994 Nobel Prize in Physiology or Medicine to Alfred G. Gilman and Martin
Rodbell for their discovery of "G-proteins and the role of these
proteins in signal transduction in cells".
The 2000 Nobel Prize in Physiology or Medicine to Eric Kandel, Arvid Carlsson
and Paul Greengard, for research on neurotransmitters such as dopamine,
which act via GPCRs. The 2004 Nobel Prize in Physiology or
Medicine to Richard Axel and Linda B. Buck for their work on G protein-coupled
olfactory receptors. The 2012 Nobel Prize in Chemistry to
Brian Kobilka and Robert Lefkowitz for their work on GPCR function.
Function G proteins are important signal
transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled
Receptor] signaling pathways are involved in many diseases, such as
diabetes, blindness, allergies, depression, cardiovascular defects, and
certain forms of cancer. It is estimated that about 30% of the modern drugs'
cellular targets are GPCRs." The human genome encodes roughly 800 G
protein-coupled receptors, which detect photons of light, hormones, growth
factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs
found in the human genome have still-unknown functions.
Whereas G proteins are activated by G protein-coupled receptors, they are
inactivated by RGS proteins. Receptors stimulate GTP binding. RGS proteins
stimulate GTP hydrolysis. Types of G protein signaling
G protein can refer to two distinct families of proteins. Heterotrimeric G
proteins, sometimes referred to as the "large" G proteins, are activated by G
protein-coupled receptors and are made up of alpha, beta, and gamma subunits.
"Small" G proteins belong to the Ras superfamily of small GTPases. These
proteins are homologous to the alpha subunit found in heterotrimers, but are
in fact monomeric, consisting of only a single unit. However, like their larger
relatives, they also bind GTP and GDP and are involved in signal transduction.
= Heterotrimeric G proteins= Different types of heterotrimeric G
proteins share a common mechanism. They are activated in response to a
conformational change in the GPCR, exchanging GDP for GTP, and dissociating
in order to activate other proteins in a particular signal transduction pathway.
The specific mechanisms, however, differ between protein types.
Common mechanism Receptor-activated G proteins are bound
to the inner surface of the cell membrane. They consist of the Gα and the
tightly associated Gβγ subunits. There are many classes of Gα subunits: Gsα,
Giα, Goα, Gq/11α, and G12/13α are some examples. They behave differently in the
recognition of the effector molecule, but share a similar mechanism of
activation. = Activation=
When a ligand activates the G protein-coupled receptor, it induces a
conformational change in the receptor that allows the receptor to function as
a guanine nucleotide exchange factor that exchanges GDP for GTP - thus
turning the GPCR "on". The GTP is bound to the Gα subunit in the traditional
view of heterotrimeric GPCR activation. This exchange triggers the dissociation
of the Gα subunit from the Gβγ dimer and the receptor as a whole. However, models
which suggest molecular rearrangement, reorganization, and pre-complexing of
effector molecules are beginning to be accepted. Both Gα-GTP and Gβγ can then
activate different signaling cascades and effector proteins, while the
receptor is able to activate the next G protein.
= Termination= The Gα subunit will eventually hydrolyze
the attached GTP to GDP by its inherent enzymatic activity, allowing it to
re-associate with Gβγ and starting a new cycle. A group of proteins called
Regulator of G protein signalling, act as GTPase-activating proteins, are
specific for Gα subunits. These proteins accelerate the hydrolysis of GTP to GDP,
thus terminating the transduced signal. In some cases, the effector itself may
possess intrinsic GAP activity, which then can help deactivate the pathway.
This is true in the case of phospholipase C-beta, which possesses
GAP activity within its C-terminal region. This is an alternate form of
regulation for the Gα subunit. However, it should be noted that such Gα GAPs do
not have catalytic residues to activate the Gα protein. They work instead by
lowering the required activation energy for the reaction to take place.
Specific mechanisms = Gαs=
Gαs activates the cAMP-dependent pathway by stimulating the production of cyclic
AMP from ATP. This is accomplished by direct stimulation of the
membrane-associated enzyme adenylate cyclase. cAMP can then act as a second
messenger that goes on to interact with and activate protein kinase A. PKA can
phosphorylate a myriad downstream targets.
The cAMP Dependent Pathway is used as a signal transduction pathway for many
hormones including: ADH - Promotes water retention by the
kidneys GHRH - Stimulates the synthesis and
release of GH GHIH - Inhibits the synthesis and
release of GH CRH - Stimulates the synthesis and
release of ACTH ACTH - Stimulates the synthesis and
release of Cortisol TSH - Stimulates the synthesis and
release of a majority of T4 LH - Stimulates follicular maturation
and ovulation in women; or testosterone production and spermatogenesis in men
FSH - Stimulates follicular development in women; or spermatogenesis in men
PTH - Increases blood calcium levels. This is accomplished via the Parathyroid
hormone 1 receptor in the kidneys and bones, or via the Parathyroid hormone 2
receptor in the central nervous system and brain, as well as the bones and
kidneys. Calcitonin - Decreases blood calcium
levels Glucagon - Stimulates glycogen breakdown
in the liver hCG - Promotes cellular differentiation,
and is potentially involved in apoptosis.
Epinephrine - released by the adrenal medulla during the fasting state, when
body is under metabolic duress. It stimulates glycogenolysis, in addition
to the actions of glucagon. = Gαi=
Gαi inhibits the production of cAMP from ATP.
Insulin works through Gi second messenger proteins.
= Gαq/11= Gαq/11 stimulates the membrane-bound
phospholipase C beta, which then cleaves PIP2 into two second messengers, IP3 and
diacylglycerol. The Inositol Phospholipid Dependent Pathway is used
as a signal transduction pathway for many hormones including:
ADH - Induces the synthesis and release of glucocorticoids; Induces
vasoconstriction TRH - Induces the synthesis and release
of TSH TSH - Induces the synthesis and release
of a small amount of T4 Angiotensin II - Induces Aldosterone
synthesis and release GnRH - Induces the synthesis and release
of FSH and LH = Gα12/13=
Gα12/13 are involved in Rho family GTPase signaling. This is through the
RhoGEF superfamily involving the RhoGEF domain of the proteins' structures).
These are involved in control of cell cytoskeleton remodeling, and thus in
regulating cell migration. = Gβ=
The Gβγ complexes sometimes also have active functions. Examples include
coupling to and activating G protein-coupled inwardly-rectifying
potassium channels. = Small GTPases=
Small GTPases also bind GTP and GDP and are involved in signal transduction.
These proteins are homologous to the alpha subunit found in heterotrimers,
but exist as monomers. They are small proteins that bind to guanosine
triphosphate. This family of proteins is homologous to the Ras GTPases and is
also called the Ras superfamily GTPases. Lipidation
In order to associate with the inner leaflet of the plasma membrane, many G
proteins and small GTPases are lipidated, that is, covalently modified
with lipid extensions. They may be myristolated, palmitoylated or
prenylated. References
External links GTP-Binding Proteins at the US National
Library of Medicine Medical Subject Headings