G-protein-coupled receptor kinase 3 (GRK3) 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 ''ADRBK2''
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 ...
.
GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), 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
GRK2.
Function
G protein-coupled receptor kinases phosphorylate 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. As a result, the G protein-coupled receptors' complicated signaling switch is the GRK/arrestin system.
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
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.
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, ...
.
Gene linkage 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 (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...
.
However, the significance of GRK3 in bipolar disorder has been controversial due to conflicting reports. GRK3 has also been implicated in regulation of
dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diff ...
s 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 immunocompromise, 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 affec ...
WHIM syndrome 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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