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G-proteins

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G-proteins

Not to be confused with Protein G.


G proteins, also known as guanosine nucleotide-binding proteins, are a family of proteins involved in transmitting signals from a variety of different 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. 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.[2] 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.[3]

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 stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP.[4] For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.[5]

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." [6]

The human genome encodes roughly 800 [7] 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 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

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.

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 (GEF) that exchanges GTP in place of GDP 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.[8][9] 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.[10]

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 (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.[11]

Specific mechanisms

Gαs

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
Gαi

Gαi inhibits the production of cAMP from ATP.

Gαq/11

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:

  • ADH (Vasopressin/AVP) - Induces the synthesis and release of glucocorticoids (zona fasiculata of adrenal cortex in kidney); Induces vasoconstriction (V1 Cells of Posterior Pituitary)
  • TRH - Induces the synthesis and release of TSH (Anterior Pituitary)
  • TSH - Induces the synthesis and release of a small amount of T4 (Thyroid Gland)
  • Angiotensin II - Induces Aldosterone synthesis and release (zona glomerulosa 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 (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration.
Gβ

Small GTPases

Main article: 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.

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

  • Medical Subject Headings (MeSH)

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