G proteins, also known as guanine nucleotide-binding proteins, are a
family of proteins
A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be c ...
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
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only diffe ...
(GTP) to
guanosine diphosphate (GDP). 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 (small G-proteins), while the second function as
heterotrimeric G protein complexes. The latter class of complexes is made up of ''
alpha
Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', or ell, άλφα, álfa) is the first letter of the Greek alphabet. In the system of Greek numerals, it has a value of one. Alpha is derived from the Phoenician letter aleph , whic ...
'' (α), ''beta'' (β) and ''gamma'' (γ)
subunit
Subunit may refer to:
*Subunit HIV vaccine, a class of HIV vaccine
*Protein subunit, a protein molecule that assembles with other protein molecules
*Monomer, a molecule that may bind chemically to other molecules to form a polymer
*Sub-subunit, a ...
s.
In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the
beta-gamma complex
.
Heterotrimeric G proteins located within the cell are activated by
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s (GPCRs) 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 active-state GPCRs have also been shown to be "pre-coupled" with G proteins, whereas in other cases a collision coupling mechanism is thought to occur.
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
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s,
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s, and other signaling factors.
G proteins regulate metabolic
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s,
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s,
transporter proteins, and other parts of the cell machinery, controlling
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
,
motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
,
contractility, and
secretion 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...
, which in turn regulate diverse systemic functions such as
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, learning and memory, and
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
.
History
G proteins were discovered in 1980 when
Alfred G. Gilman
Alfred Goodman Gilman (July 1, 1941 – December 23, 2015) was an American pharmacologist and biochemist. He and Martin Rodbell shared the 1994 Nobel Prize in Physiology or Medicine "for their discovery of G-proteins and the role of these prot ...
and
Martin Rodbell investigated stimulation of cells by
adrenaline. They found that when adrenaline binds to a receptor, the receptor does not stimulate enzymes (inside the cell) directly. Instead, the receptor stimulates a G protein, which then stimulates an enzyme. An example is
adenylate cyclase, which produces the
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
.
[The Nobel Prize in Physiology or Medicine 1994](_blank)
Illustrated Lecture. For this discovery, they won the 1994
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
.
Nobel prizes have been awarded for many aspects of signaling by G proteins and GPCRs. These include
receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...
s,
neurotransmitters, neurotransmitter
reuptake,
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, G proteins,
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
s, the enzymes that trigger protein
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
in response to
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, and consequent metabolic processes such as
glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
The ...
.
Prominent examples include (in chronological order of awarding):
* The 1947
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Carl Cori,
Gerty Cori and
Bernardo Houssay
Bernardo Alberto Houssay (April 10, 1887 – September 21, 1971) was an Argentine physiologist. Houssay was a co-recipient of the 1947 Nobel Prize for Physiology or Medicine for discovering the role played by pituitary hormones in regulating th ...
, for their discovery of how
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
is broken down to
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
and resynthesized in the body, for use as a store and source of energy.
Glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
The ...
is stimulated by numerous
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s and
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s including
adrenaline.
* The 1970
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Julius Axelrod
Julius Axelrod (May 30, 1912 – December 29, 2004) was an American biochemist. He won a share of the Nobel Prize in Physiology or Medicine in 1970 along with Bernard Katz and Ulf von Euler. The Nobel Committee honored him for his work on the re ...
,
Bernard Katz
Sir Bernard Katz, Fellow of the Royal Society, FRS (; 26 March 1911 – 20 April 2003) was a German-born British people, British physician and biophysics, biophysicist, noted for his work on nerve physiology. He shared the Nobel Prize in Physiol ...
and
Ulf von Euler for their work on the release and
reuptake of
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s.
* The 1971
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Earl Sutherland
Earl Wilbur Sutherland Jr. (November 19, 1915 – March 9, 1974) was an American pharmacologist and biochemist born in Burlingame, Kansas. Sutherland won a Nobel Prize in Physiology or Medicine in 1971 "for his discoveries concerning the mechanis ...
for discovering the key role of
adenylate cyclase, which produces the second messenger
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
.
* The 1988
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
George H. Hitchings
George Herbert Hitchings (April 18, 1905 – February 27, 1998) was an American medical doctor who shared the 1988 Nobel Prize in Physiology or Medicine with Sir James Black and Gertrude Elion "for their discoveries of important principles for ...
,
Sir James Black
Sir James Whyte Black (14 June 1924 – 22 March 2010) was a Scottish physician and pharmacologist. Together with Gertrude B. Elion and George H. Hitchings, he shared the Nobel Prize for Medicine in 1988 for pioneering strategies for rational d ...
and
Gertrude Elion
Gertrude "Trudy" Belle Elion (January 23, 1918 – February 21, 1999) was an American biochemist and pharmacologist, who shared the 1988 Nobel Prize in Physiology or Medicine with George H. Hitchings and Sir James Black for their use of innovati ...
"for their discoveries of important principles for drug treatment" targeting GPCRs.
* The 1992
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Edwin G. Krebs
Edwin Gerhard Krebs (June 6, 1918 – December 21, 2009) was an American biochemist. He received the Albert Lasker Award for Basic Medical Research and the Louisa Gross Horwitz Prize of Columbia University in 1989 together with Alfred Gilman and ...
and
Edmond H. Fischer for describing how reversible
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
works as a switch to activate
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s, and to regulate various cellular processes including
glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
The ...
.
* The 1994
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Alfred G. Gilman
Alfred Goodman Gilman (July 1, 1941 – December 23, 2015) was an American pharmacologist and biochemist. He and Martin Rodbell shared the 1994 Nobel Prize in Physiology or Medicine "for their discovery of G-proteins and the role of these prot ...
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
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Eric Kandel,
Arvid Carlsson
Arvid Carlsson (25 January 1923 – 29 June 2018) was a Swedish neuropharmacologist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease. For his work on dopamine, Carlsson was awarded the No ...
and
Paul Greengard
Paul Greengard (December 11, 1925 – April 13, 2019) was an American neuroscientist best known for his work on the molecular and cellular function of neurons. In 2000, Greengard, Arvid Carlsson and Eric Kandel were awarded the Nobel Prize for Ph ...
, for research on
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s such as
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
, which act via GPCRs.
* The 2004
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
to
Richard Axel
Richard Axel (born July 2, 1946) is an American molecular biologist and university professor in the Department of Neuroscience at Columbia University and investigator at the Howard Hughes Medical Institute. His work on the olfactory system won hi ...
and
Linda B. Buck for their work on G protein-coupled
olfactory receptors.
* The 2012
Nobel Prize in Chemistry
)
, image = Nobel Prize.png
, alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
to
Brian Kobilka
Brian Kent Kobilka (born May 30, 1955) is an American physiologist and a recipient of the 2012 Nobel Prize in Chemistry with Robert Lefkowitz for discoveries that reveal the workings of G protein-coupled receptors. He is currently a professor in ...
and
Robert Lefkowitz for their work on GPCR function.
Function
G proteins are important
signal transducing molecules in cells. "Malfunction of GPCR
Protein-Coupled Receptorsignaling pathways are involved in many diseases, such as
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, blindness, allergies, depression, cardiovascular defects, and certain forms of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. 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
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
. Approximately 150 of the GPCRs found in the human genome still have unknown functions.
Whereas G proteins are activated by
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, they are inactivated by
RGS proteins (for "Regulator of G protein signalling"). Receptors stimulate GTP binding (turning the G protein on). RGS proteins stimulate GTP hydrolysis (creating GDP, thus turning the G protein off).
Diversity
All eukaryotes use G proteins for signaling and have evolved a large diversity of G proteins. For instance, humans encode 18 different G
α proteins, 5 G
β proteins, and 12 G
γ proteins.
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 receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s and are made up of alpha (α), beta (β), and gamma (γ)
subunit
Subunit may refer to:
*Subunit HIV vaccine, a class of HIV vaccine
*Protein subunit, a protein molecule that assembles with other protein molecules
*Monomer, a molecule that may bind chemically to other molecules to form a polymer
*Sub-subunit, a ...
s. ''"Small" G proteins'' (20-25kDa) belong to the
Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
superfamily of
small GTPases. These proteins are
homologous to the alpha (α) 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
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
.
Heterotrimeric
Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
in the GPCR, exchanging GDP for GTP, and dissociating in order to activate other proteins in a particular
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathway. The specific mechanisms, however, differ between protein types.
Mechanism
Receptor-activated G proteins are bound to the inner surface of the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. They consist of the G
α and the tightly associated G
βγ subunits. There are many classes of G
α subunits: G
sα (G stimulatory), G
iα (G inhibitory), G
oα (G other), G
q/11α, and G
12/13α are some examples. They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation.
Activation
When a
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
activates the
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
, it induces a conformational change in the receptor that allows the receptor to function as a
guanine nucleotide exchange factor
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...
(GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the G
α subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the G
α subunit (which is bound to GTP) from the G
βγ 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 G
α-GTP and G
βγ can then activate different ''signaling cascades'' (or ''
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
pathways'') and effector proteins, while the receptor is able to activate the next G protein.
Termination
The G
α subunit will eventually
hydrolyze
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis ...
the attached GTP to GDP by its inherent
enzymatic
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
activity, allowing it to re-associate with G
βγ and starting a new cycle. A group of proteins called
Regulator of G protein signalling
Regulators of G protein signaling (RGS) are protein structural domains or the proteins that contain these domains, that function to activate the GTPase activity of heterotrimeric G-protein α-subunits.
RGS proteins are multi-functional, GTPase-a ...
(RGSs), act as
GTPase-activating proteins (GAPs), are specific for G
α 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
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
-beta, which possesses GAP activity within its
C-terminal region. This is an alternate form of regulation for the G
α subunit. Such G
α GAPs do not have catalytic residues (specific amino acid sequences) to activate the G
α protein. They work instead by lowering the required
activation energy
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
for the reaction to take place.
Specific mechanisms
=Gαs
=
Gαs activates the
cAMP-dependent pathway by stimulating the production of
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP) from
ATP
ATP may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
. 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). 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 (created by the
magnocellular neurosecretory cell
Magnocellular neurosecretory cells are large neuroendocrine cells within the supraoptic nucleus and paraventricular nucleus of the hypothalamus. They are also found in smaller numbers in accessory cell groups between these two nuclei, the largest ...
s of the
posterior pituitary)
*
GHRH – Stimulates the synthesis and release of GH (
somatotropic cell
Somatotropes (from the Greek ''sōmat'' meaning "body" and ''tropikós'' meaning "of or pertaining to a turn or change") are cells in the anterior pituitary that produce growth hormone.
Structure
Somatotropic cells constitute about 30−40% of ant ...
s of the
anterior pituitary
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
)
*
GHIH
Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
– Inhibits the synthesis and release of GH (somatotropic cells of anterior pituitary)
*
CRH CRH may refer to:
* Calibre radius head, a traditional British ordnance term for a concept in ballistic projectile design
* Celtic Resources Holdings, an Irish mining company
* China Railway High-speed, a high-speed railway service operated by Chin ...
– Stimulates the synthesis and release of ACTH (anterior pituitary)
*
ACTH – Stimulates the synthesis and release of
cortisol
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
(
zona fasciculata of the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
in the adrenal glands)
*
TSH – Stimulates the synthesis and release of a majority of
T4 (thyroid gland)
*
LH – Stimulates follicular maturation and ovulation in women; or testosterone production and spermatogenesis in men
*
FSH – Stimulates follicular development in women; or
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
in men
*
PTH – Increases
blood calcium
Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...
levels. This is accomplished via the
parathyroid hormone 1 receptor
Parathyroid hormone/parathyroid hormone-related peptide receptor, also known as parathyroid hormone 1 receptor (PTH1R), is a protein that in humans is encoded by the ''PTH1R'' gene. PTH1R functions as a receptor for parathyroid hormone ( PTH) and f ...
(PTH1) in the kidneys and bones, or via the
parathyroid hormone 2 receptor
Parathyroid hormone 2 receptor is a protein that in humans is encoded by the ''PTH2R'' gene.
Function
The protein encoded by this gene is a member of the G protein-coupled receptor family 2. This protein is a receptor for parathyroid hormone (P ...
(PTH2) in the central nervous system and brain, as well as the bones and kidneys.
*
Calcitonin
Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates. in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...
– Decreases blood calcium levels (via the
calcitonin receptor in the intestines, bones, kidneys, and brain)
*
Glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
– Stimulates
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
breakdown in the liver
*
hCG – Promotes cellular differentiation, and is potentially involved in
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
*
Epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
– released by the ''
adrenal medulla
The adrenal medulla ( la, medulla glandulae suprarenalis) is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cel ...
'' during the fasting state, when body is under metabolic duress. It stimulates
glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
The ...
, in addition to the actions of
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
.
=Gαi
=
Gαi inhibits the production of cAMP from ATP.
e.g. somatostatin, prostaglandins
=Gαq/11
=
Gαq/11 stimulates the membrane-bound
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
beta, which then cleaves PIP
2 (a minor membrane
phosphoinositol) into two second messengers,
IP3 and
diacylglycerol (DAG).
The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:
* ADH (
Vasopressin/AVP) – Induces the synthesis and release of
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
s (
Zona fasciculata of
adrenal cortex
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
); Induces vasoconstriction (V1 Cells of
Posterior pituitary)
* TRH – Induces the synthesis and release of TSH (
Anterior pituitary gland
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...
)
* TSH – Induces the synthesis and release of a small amount of T4 (
Thyroid Gland
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobe (anatomy), lobes. The lower two thirds of the lobes are connected by a thin band of Connective tissue, tissue cal ...
)
* Angiotensin II – Induces Aldosterone synthesis and release (
zona glomerulosa
The ''zona glomerulosa'' (sometimes, glomerular zone) of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. Its cells are ovoid and arranged in clusters or arches (''glomus'' is Latin ...
of adrenal cortex in kidney)
* GnRH – Induces the synthesis and release of FSH and LH (Anterior Pituitary)
=Gα12/13
=
*
Gα12/13 are involved in Rho family GTPase signaling (see
Rho family of GTPases). 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 channel
The G protein-coupled inwardly-rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ...
s.
Small GTPases
Small GTPases, also known as small G-proteins, bind GTP and GDP likewise, and are involved in
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
. 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
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s that bind to guanosine triphosphate (
GTP). 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
myristoylated
Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminal glycine residue. Myristic acid is a 14-carbon saturated fatty ac ...
,
palmitoylated
Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically membrane protein ...
or
prenylated
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
.
References
External links
*
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Peripheral membrane proteins
Cell signaling
Signal transduction
EC 3.6