G-protein-coupled receptor kinase 2 (GRK2) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that in humans is encoded by the ''ADRBK1''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the
G protein-coupled receptor kinase 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 fu ...
s that is most highly similar to
GRK3(βARK2).
Functions
G protein-coupled receptor kinases
phosphorylate
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, ...
activated G protein-coupled receptors, which promotes the binding of an
arrestin 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 heterotrimeric complex. The biggest non-structu ...
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 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 ...
, 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 referen ...
), 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 beta ...
, 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 p ...
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, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
.
Strategies to inhibit GRK2 include using small molecules (including
Paroxetine
Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
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 protein
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 ...
s) to turn off G protein signaling.
Interactions
GRK2 has been shown to
interact with numerous protein partners,
including:
*
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 ...
βγ complex
*
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 ...
GNAQ 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 prot ...
and
GIT2
*
PDE6G
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma is an enzyme that in humans is encoded by the ''PDE6G'' gene.
Interactions
PDE6G has been shown to interact with Beta adrenergic receptor kinase and Src.
...
*
PRKCB1
*
Src
See also
*
G protein-coupled receptor kinases
*
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 ...
*
desensitization (medicine)
*
arrestin
*
Kinase
In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
References
External links
*
*
*
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Proteins
EC 2.7.11
Transferases
Protein kinases