G-protein-coupled receptor kinase 3 (GRK3) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''ADRBK2''
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 ba ...
.
GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the
G protein-coupled receptor kinase subfamily of the Ser/Thr
protein kinases that is most highly similar to
GRK2.
Function
G protein-coupled receptor kinases phosphorylate 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 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.
GRK3 and the closely related GRK2 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
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 ...
(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.
GRK3 is expressed broadly in tissues, but generally at lower levels than the related GRK2. GRK3 has particularly high expression in olfactory neurons, and mice lacking the ADRBK2 gene exhibit defects in
olfaction
The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste.
In humans, it ...
.
Gene linkage
Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separ ...
techniques were used to identify a polymorphism in the promoter of the human ADRBK2 gene as a possible cause of up to 10% of cases of
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
.
However, the significance of GRK3 in bipolar disorder has been controversial due to conflicting reports. GRK3 has also been implicated in regulation of
dopamine receptors in
Parkinson disease Parkinson may refer to:
*Parkinson (surname)
* ''Parkinson'' (TV series), British chat show, presented by Sir Michael Parkinson
*Parkinson, Queensland, suburb of Brisbane, Australia
*The Parkinsons (fl. early 20th century), American father-and-son ...
in animal models. Reduced expression of GRK3 has been associated with the
immunodeficient
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
WHIM syndrome
WHIM syndrome (or Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.
Pathophysiology
WHIM syndrome results from autosomal dom ...
in humans, and appears causative in a mouse model of the disease.
References
Further reading
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External links
Online version of the paper in ''Molecular Psychiatry''PubMed abstract*
{{Portal bar, Biology, border=no
Biology of bipolar disorder
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