This gene encodes 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 ...

family, and is most highly similar to

GRK4 G protein-coupled receptor kinase 4 (GRK4) is an enzyme that is encoded by the ''GRK4'' gene in humans. This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most similar to G ...

and

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 ...

. The protein

phosphorylates 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 ...

the activated forms of

G protein-coupled receptors 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 protein family, group of evoluti ...

to regulate their

signaling A signal is both the process and the result of transmission of data over some media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processing, information theory and biology. ...

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. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors. GRK6 and the closely related GRK5 phosphorylate receptors at sites that encourage arrestin-mediated signaling rather than arrestin-mediated receptor desensitization, internalization and trafficking (in contrast to

GRK2 G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ''ADRBK1'' gene. GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the G protein-coupled receptor kinase subfam ...

and

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 ...

, 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 reference ligand (often the end ...

(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. GRK6 is widely and relatively evenly expressed throughout the body, but with particularly high expression in immune cells. GRK6 exists in three splice variants that differ in the carboxyl terminal region that regulates membrane association: one form is palmitoylated, another contains a lipid-binding polybasic domain, and the third is truncated and has neither. In the mouse, GRK6 regulates the D2

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 ...

in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

region of the brain, and loss of GRK6 leads to increased sensitivity to

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

drugs that act through dopamine. Overexpression of GRK6 in the striatum in a rat model of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

improves drug-induced movement disorder (

tardive dyskinesia Tardive dyskinesia (TD) is an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...

) symptoms arising from

L-DOPA -DOPA, also known as -3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DO ...

therapy. In mouse immune cells, GRK6 is important for chemotaxis of

B-lymphocytes B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

and

T-lymphocytes T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

in response to the

chemoattractant Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

CXCL12 The stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the ''CXCL12'' gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types. St ...

, and of

neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

to sites of injury in response to

leukotriene B4 Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice. Biochemistry LTB4 is a leukotriene involved in inflammation. It is produced from leukocytes in response to inflammato ...

Function

References

Further reading