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 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(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 and
GRK6, 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 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
*
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), ...
GNAQ family members
*
GIT1 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
See also
*
G protein-coupled receptor kinases
*
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), ...
*
desensitization (medicine)
In medicine, desensitization is a method to reduce or eliminate an organism's negative reaction to a substance or stimulus.
In pharmacology, ''drug desensitization'' refers to two related concepts. First, desensitization may be equivalent to drug ...
*
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 ...
*
Kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
References
External links
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{{Portal bar, Biology, border=no
Proteins
EC 2.7.11
Transferases
Protein kinases