G-protein-coupled receptor kinase 2 (GRK2) is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''ADRBK1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the

G protein-coupled receptor kinase G protein-coupled receptor kinases (GPCRKs, GRKs) are a family of protein kinases within the AGC ( protein kinase A, protein kinase G, protein kinase C) group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Thre ...

subfamily of the Ser/Thr

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...

s that is most highly similar to

GRK3 G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ''ADRBK2'' gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily o ...

(βARK2).

Functions

G protein-coupled receptor kinases

phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

activated G protein-coupled receptors, which promotes the binding of an

arrestin Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered in the late '80s as a part of a conserved two-step mechanism for regulatin ...

protein to the receptor. Arrestin binding to phosphorylated, active receptor prevents receptor stimulation of

heterotrimeric G protein Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a Heteromer, heterotrimeric complex. The biggest no ...

transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors. GRK2 and the closely related GRK3 phosphorylate receptors at sites that encourage arrestin-mediated receptor desensitization, internalization and trafficking rather than arrestin-mediated signaling (in contrast to

GRK5 G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6. The protein phosphorylates the activated forms of G protein-coupled re ...

and

GRK6 This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most highly similar to GRK4 and GRK5. The protein phosphorylates the activated forms of G protein-coupled receptors to reg ...

, which have the opposite effect). This difference is one basis for pharmacological biased agonism (also called

functional selectivity Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...

), where a drug binding to a receptor may bias that receptor’s signaling toward a particular subset of the actions stimulated by that receptor. GRK2 is expressed broadly in tissues, but generally at higher levels than the related GRK3. GRK2 was originally identified as a protein kinase that phosphorylated the β2-

adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like b ...

, and has been most extensively studied as a regulator of adrenergic receptors (and other

GPCR 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 ...

s) in the heart, where it has been proposed as a drug target to treat

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. Strategies to inhibit GRK2 include using small molecules (including

Paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

and Compound-101) and using gene therapy approaches utilizing regulatory domains of GRK2 (particularly overexpressing the carboxy terminal pleckstrin-homology (PH) domain that binds the G protein βγ-subunit complex and inhibits GRK2 activation (often called the “ βARKct”), or just a peptide from this PH domain). GRK2 and the related GRK3 can interact with heterotrimeric G protein subunits resulting from GPCR activation, both to be activated and to regulate G protein signaling pathways. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein βγ subunits, and GPCR activation of heterotrimeric G proteins releases this free βγ complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor. The amino terminal RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family to reduce Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta; but the GRK2 and GRK3 RH domains are unable to function as GTPase-activating proteins (as do traditional RGS proteins) to turn off G protein signaling.

Interactions

GRK2 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with numerous protein partners, including: *

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

βγ complex *

GNAQ Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the ''GNAQ'' gene. Together with GNA11 (its paralogue), it functions as a Gq alpha subunit. Function Guanine nucleotide-binding proteins are a fam ...

family members *

GIT1 ARF GTPase-activating protein GIT1 is an enzyme that in humans is encoded by the ''GIT1'' gene. GIT1 contains an ARFGAP domain, Anykrin repeats, and a GRK-interacting domain. The Arf-GAP domain, which enables it to act as a GTPase activating pr ...

and GIT2 * PDE6G *

PRKCB1 Protein kinase C beta type is an enzyme that in humans is encoded by the ''PRKCB'' gene. Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and second messenger diacylglycerol. PK ...

* Src

References

External links

* * * {{Portal bar, Biology, border=no Proteins EC 2.7.11 Transferases Protein kinases

Functions

Interactions

See also

References

External links