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G protein

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G protein

Phosducin- transducin beta-gamma complex. Beta and gamma subunits of G-protein are shown by blue and red, respectively.

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins involved in transmitting signals from a variety of stimuli outside a cell into the inside of the cell. G proteins function as molecular switches. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they bind GTP, they are 'on', and, when they bind 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 are made up of alpha (α), beta (β) and gamma (γ) subunits.[1] 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 (GPCRs) that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell. An intracellular GPCR domain in turn activates a G protein. Some inactive-state GPCRs are also shown to be pre-coupled with G proteins.[2]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.[3] 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.[4]


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 stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP.[5] For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.[6]

Nobel prizes have been awarded for most aspects of signaling by G proteins and G protein-coupled receptors. 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 2000 Nobel Prize in Physiology or Medicine to Eric Kandel, Arvid Carlsson and Paul Greengard for their research on neurotransmitters such as dopamine, which act via G protein-coupled receptors.

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 1988 Sir James Black and Gertrude Elion "for their discoveries of important principles for drug treatment" targeting G protein-coupled receptors.

The 2012 Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz for their work on G protein–coupled receptor function. [7]

The 2004 Nobel Prize in Physiology or Medicine to Richard Axel and Linda B. Buck for their work on G protein-coupled olfactory receptors.[8]

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". [9]

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. [10]

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 regulate various cellular processes including glycogenolysis.[11]

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.


G proteins are important signal transducing molecules in cells.[12] "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." [13]

The human genome encodes roughly 800 [14] 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.

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 that are activated by G protein-coupled receptors and made up of alpha (α), beta (β), and gamma (γ) subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. 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.

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 receptor, exchange GDP for GTP, and dissociate to activate other proteins in the signal transduction pathway. The specific mechanisms, however, differ among the types.

Common mechanism

Activation cycle of a G-protein (purple) by a G-protein-coupled receptor (light blue) receiving a ligand (red).

Receptor-activated G proteins are bound to the inside surface of the cell membrane. 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.


When a [2][15][16] 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.[17]


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 (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 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 the Gα GAPs do not have catalytic residues to activate the Gα protein. It works instead by lowering the required activation energy for the reaction to take place.[18]

Specific mechanisms


Gαs activates the cAMP-dependent pathway by stimulating the production of cAMP from ATP. This is accomplished by direct stimulation of the membrane-associated enzyme adenylate cyclase. cAMP acts as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can then 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 (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 apoptosis
  • Epinephrine - released during the fasting state when body is under metabolic duress (released by adrenal medulla). Stimulates glycogenolysis along with Glucagon.

Gαi inhibits the production of cAMP from ATP.

Insulin works through Gi (inhibitory) second messenger proteins.


Gαq/11 stimulates membrane-bound phospholipase C beta, which then cleaves PIP2 (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:

  • Gα12/13 are involved in Rho family GTPase signaling (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration.

Small GTPases

Small GTPases also bind GTP and GDP and are involved in signal transduction. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but exist as monomers. They are small (20-kDa to 25-kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and is also called the Ras superfamily GTPases.


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.


  1. ^ Hurowitz EH, Melnyk JM, Chen YJ, Kouros-Mehr H, Simon MI, Shizuya H (2000). "Genomic characterization of the human heterotrimeric G protein alpha, beta, and gamma subunit genes". DNA Res 7 (2): 111–20.  
  2. ^ a b Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology 7 (11): 740–747.  
  3. ^ Reece J, C N (2002). Biology. San Francisco: Benjamin Cummings.  
  4. ^ Neves SR, Ram PT, Iyengar R (May 2002). "G protein pathways". Science 296 (5573): 1636–9.  
  5. ^ The Nobel Prize in Physiology or Medicine 1994, Illustrated Lecture.
  6. ^ Press Release: The Nobel Assembly at the Karolinska Institute decided to award the Nobel Prize in Physiology or Medicine for 1994 jointly to Alfred G. Gilman and Martin Rodbell for their discovery of "G-proteins and the role of these proteins in signal transduction in cells". 10 October 1994
  7. ^ Royal Swedish Academy of Sciences (10 October 2012). "The Nobel Prize in Chemistry 2012 Robert J. Lefkowitz, Brian K. Kobilka". Retrieved 10 October 2012. 
  8. ^
  9. ^ Press Release:
  10. ^ The Nobel Prize in Physiology or Medicine 1994, Illustrated Lecture.
  11. ^ "The Nobel Prize in Physiology or Medicine 1992 Press Release".  
  12. ^ Servin JA, Campbell AJ, Borkovich KA. (2012). G Protein Signaling Components in Filamentous Fungal Genomes. In: Witzany G (ed). Biocommunication of Fungi. Springer; 21-38. ISBN 978-94-007-4263-5.
  13. ^ Bosch DE, Siderovski DP (2013). "G protein signaling in the parasite Entamoeba histolytica". Experimental & Molecular Medicine 10 (1038): 1–12. 
  14. ^ Baltoumas FA, Theodoropoulou MC, Hamodrakes SJ (2013). "Interactions of the alpha subunits of heterotrimeric G-proteins with GPCRs, effectors and RGS proteins: A critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials". Journal of Structural Biology 10 (1016). 
  15. ^ Digby GJ, Lober RM, Sethi PR, Lambert NA (2006). "Some G protein heterotrimers physically dissociate in living cells". Proc Natl Acad Sci USA 103 (47): 17789–94.  
  16. ^
  17. ^
  18. ^ Sprang SR, Chen Z, Du X (2007). "Structural basis of effector regulation and signal termination in heterotrimeric Galpha proteins.". Advances in protein chemistry 74: 1–65.  

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