G protein
Encyclopedia
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors.
G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s are transmembrane receptors. Signal molecules bind to a domain located outside the cell. An intracellular domain activates a G protein. The G protein activates a cascade of further compounds, and finally causes a change downstream in the cell.
G proteins function as molecular switches. When they bind guanosine triphosphate (GTP), they are 'on', and, when they bind guanosine diphosphate (GDP), they are 'off'.
G proteins regulate metabolic enzymes, ion channels, transporters, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate systemic functions such as embryonic development, learning and memory, and homeostasis.
G proteins were discovered when Alfred G. Gilman
Alfred G. Gilman
Alfred Goodman Gilman is an American pharmacologist and biochemist. He shared the 1994 Nobel Prize in Physiology or Medicine with Martin Rodbell for their discoveries regarding G-proteins....
and Martin Rodbell
Martin Rodbell
Martin Rodbell was an American biochemist and molecular endocrinologist who is best known for his discovery of G-proteins. He shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G...
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 stimulates an enzyme. An example is adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
, which produces the second messenger cyclic AMP. For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
.
G proteins belong to the larger group of enzymes called GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
s.
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 cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. It is estimated that more than half of the modern drugs' cellular targets are GPCRs."
The human genome encodes roughly 950 G protein-coupled receptors, which detect photons (light), hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.
Types of G protein signaling
G protein can refer to two distinct families of proteins. Heterotrimeric G proteinHeterotrimeric G protein
"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha , beta and gamma subunits, the latter two referred to as the beta-gamma...
s, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s and made up of alpha (α), beta (β), and gamma (γ) subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
s. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPase
Small GTPase
Small GTPases are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . They are a form of G-proteins found in the cytosol which are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function...
s. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
.
Heterotrimeric G proteins
Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a conformation change in the G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
, exchange GDP for GTP, and dissociate to activate other proteins in the signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathway. The specific mechanisms, however, differ among the types.
Common mechanism
Receptor-activated G proteins are bound to the inside surface of the cell membraneCell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. They consist of the Gα and the tightly associated Gβγ subunits. There are many classes of Gα subunits: Gsα (G stimulatory), Giα (G inhibitory), Goα (G other), Gq/11α, and G12/13α are some examples. They behave differently in the recognition of the effector, but share a similar mechanism of activation.
Activation
When a ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
activates the G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
(GEF) that exchanges GDP for GTP on the Gα subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the Gα subunit, bound to GTP, from the Gβγ dimer and the receptor. However, models that 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 (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.
Termination
The Gα subunit will eventually hydrolyze
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
the attached GTP to GDP by its inherent enzymatic
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
activity, allowing it to re-associate with Gβγ and starting a new cycle. A group of proteins called Regulator of G protein signalling
Regulator of G protein signalling
Regulators of G protein signalling are protein structural domains that activate GTPases for heterotrimeric G-protein alpha-subunits....
(RGSs), act as GTPase-activating proteins (GAPs), specific for Gα subunits. These proteins act to accelerate hydrolysis of GTP to GDP and terminate the transduced signal. In some cases, the effector itself may possess intrinsic GAP activity, which helps deactivate the pathway. This is true in the case of phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
beta, which possesses GAP activity within its C-terminal region. This is an alternate form of regulation for the Gα subunit.
Specific mechanisms
- Gαs activates the cAMP-dependent pathway by stimulating the production of cAMP from ATPAdenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. This is accomplished by direct stimulation of the membrane-associated enzyme adenylate cyclaseAdenylate cyclaseAdenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
. cAMP acts as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can then phosphorylate 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 (V2 Cells of Posterior Pituitary)
- GHRH - Stimulates the synthesis and release of GH (Somatotroph Cells of Anterior Pituitary)
- GHIH - Inhibits the synthesis and release of GH (Somatotroph Cells of Anterior Pituitary)
- CRH - Stimulates the synthesis and release of ACTH (Anterior Pituitary)
- ACTH - Stimulates the synthesis and release of Cortisol (zona fasiculata of adrenal cortex in kidneys)
- TSH - Stimulates the synthesis and release of a majority of T4 (Thyroid Gland)
- LH - Stimulates follicular maturation and ovulation in women; Stimulates testosterone production and spermatogenesis in men
- FSH - Stimulates follicular development in women; Stimulates spermatogenesis in men
- PTH - Increases blood calcium levels (PTH1 Receptor: Kidneys and Bone; PTH2 Receptor: Central Nervous system, Bones, Kidneys, Brain)
- Calcitonin - Decreases blood calcium levels (Calcitonin Receptor: Intestines, Bones, Kidneys, Brain)
- Glucagon - Stimulates glycogen breakdown (liver)
- hCG - Promotes cellular differentiation; Potentially involved in apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
- Gαi inhibits the production of cAMP from ATP.
- Gαq/11 stimulates membrane-bound phospholipase CPhospholipase CPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
beta, which then cleaves PIP2 (a minor membrane phosphoinositol) into two second messengers, IP3 and diacylglycerolDiglycerideA diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
(DAG).
The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:
- ADH (VasopressinVasopressinArginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
/AVP) - Induces the synthesis and release of glucocorticoidGlucocorticoidGlucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s (zona fasiculata of adrenal cortexAdrenal cortexSituated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
in kidneyKidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
); Induces vasoconstriction (V1 Cells of Posterior PituitaryPosterior pituitaryThe posterior pituitary comprises the posterior lobe of the pituitary gland and is part of the endocrine system. Despite its name, the posterior pituitary gland is not a gland, per se; rather, it is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior...
) - TRH - Induces the synthesis and release of TSH (Anterior PituitaryAnterior pituitaryA major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
) - TSH - Induces the synthesis and release of a small amount of T4 (Thyroid Gland)
- Angiotensin II - Induces Aldosterone synthesis and release (zona glomerulosaZona glomerulosaThe zona glomerulosa of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the adrenal gland's capsule...
of adrenal cortex in kidney) - GnRH - Induces the synthesis and release of FSH and LH (Anterior Pituitary)
- Gα12/13G12/G13 alpha subunitsG12/G13 subunits are alpha units of heterotrimeric G proteins that regulate cell processes through the use of guanine nucleotide exchange factors. These two subunits represent a fourth class of G protein alpha subunits. They are not sensitive to pertussis toxin.G proteins G12 and G13 regulate...
are involved in Rho family GTPase signaling (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration. - GβγBeta-gamma complex]]The beta-gamma complex is composed of the heterotrimeric G proteins Gβ and Gγ that are closely bound to one another....
sometimes also have active functions, e.g., coupling to and activating G protein-coupled inwardly-rectifying potassium channelG protein-coupled inwardly-rectifying potassium channelThe G protein-coupled inwardly-rectifying potassium channels are a family of inward-rectifier potassium ion channels which are activated via a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors . GPCRs in turn release activated G-protein βγ- subunits from...
s.
Small GTPases
Small GTPases also bind GTP and GDP and are involved in signal transductionSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but exist as monomers. They are small (20-kDa to 25-kDa) protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that bind to guanosine triphosphate (GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
). This family of proteins is homologous
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
to Ras GTPases and is also called the Ras superfamily GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
s.