Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric

small GTPase Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotri ...

s) are membrane-associated

G protein 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 act ...

s that form a

heterotrimeric In biochemistry, a protein trimer is a macromolecular Complex (chemistry), complex formed by three, usually covalent bond, non-covalently bound, macromolecules like proteins or nucleic acids. A homotrimer would be formed by three identical molecul ...

complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called

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, directly. These G proteins are made up of ''alpha'' (α), ''beta'' (β) and ''gamma'' (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein. When ligands bind a GPCR, the GPCR acquires GEF (

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 ...

) ability, which activates the G-protein by exchanging the GDP on the ''alpha'' subunit to GTP. The binding of GTP to the ''alpha'' subunit results in a structural change and its dissociation from the rest of the G-protein. Generally, the ''alpha'' subunit binds membrane-bound effector proteins for the downstream signaling cascade, but the beta-gamma complex can carry out this function also. G-proteins are involved in pathways such as the cAMP/PKA pathway, ion channels, MAPK, PI3K. There are four main families of G proteins: Gi/Go, Gq, Gs, and G12/13.

Alpha subunits

Reconstitution experiments carried out in the early 1980s showed that purified G_α subunits can directly activate effector enzymes. The GTP form of the α subunit of transducin (G_t) activates the cyclic GMP phosphodiesterase from retinal rod outer segments, and the GTP form of the α subunit of the stimulatory G protein (G_s) activates hormone-sensitive adenylate cyclase. More than one type of G protein co-exist in the same tissue. For example, in adipose tissues, two different G-proteins with interchangeable beta-gamma complexes are used to activate or inhibit adenylyl cyclase. The ''alpha'' subunit of a stimulatory G protein activated by receptors for stimulatory hormones could stimulate adenylyl cyclase, which activates cAMP used for downstream signal cascades. While on the other hand, the ''alpha'' subunit of an inhibitory G protein activated by receptors of inhibitory hormones could inhibit adenylyl cyclase, which blocks downstream signal cascades. G_α subunits consist of two domains, the GTPase domain, and the

alpha-helical The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...

domain. There exist at least 20 different G_α subunits, which are separated into four main groups. This nomenclature is based on their sequence homologies:

G beta-gamma complex

The β and γ subunits are closely bound to one another and are referred to as the

G beta-gamma complex The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanosine nucleotide-binding proteins, c ...

. Both ''beta'' and ''gamma'' subunits have different isoforms, and some combination of isoforms result in dimerization while other combinations do not. For example, ''beta1'' binds both gamma subunits while ''beta3'' binds neither. Upon activation of the GPCR, the G_βγ complex is released from the G_α subunit after its GDP-GTP exchange.

Function

The free G_βγ complex can act as a signaling molecule itself, by activating other second messengers or by gating

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 directly. For example, the G_βγ complex, when bound to

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

receptors, can activate

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...

A₂. G_βγ complexes bound to

muscarinic Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

receptors, on the other hand, directly open G protein-coupled inward rectifying potassium channels (GIRKs). When acetylcholine is the extracellular ligand in the pathway, the heart cell hyperpolarizes normally to decrease heart muscle contraction. When substances such as muscarine act as ligands, the dangerous amount of hyperpolarization leads to hallucination. Therefore, proper functioning of G_βγ plays a key role in our physiological well-being. The last function is activating

L-type calcium channels The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This c ...

, as in H₃ receptor pharmacology.

Heterotrimeric G-proteins in Plants

Heterotrimeric G-protein signaling in plants deviates from the metazoan model at various levels. For example, the presence of extra-Large G alpha, loss of G alpha and Regulator of G-protein signaling (RGS) in many plant lineages. In addition, the G-proteins are not essential for the survival in dicotyledonous plants, while they are essential for the survival of monocotyledonous plants.

References

External links

* * {{Portal bar, Biology, border=no * Peripheral membrane proteins EC 3.6.5