Beta adrenergic receptor kinase

GRK2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4PNK, 1BAK, 3CIK, 3KRW, 3KRX, 3V5W, 4MK0, 5HE1
Identifiers
Aliases	GRK2, BARK1, BETA-ARK1, ADRBK1, G protein-coupled receptor kinase 2
External IDs	MGI: 87940 HomoloGene: 1223 GeneCards: GRK2
Targeted by Drug
balanol[1]
Gene ontology Molecular function • transferase activity • Edg-2 lysophosphatidic acid receptor binding • protein kinase activity • nucleotide binding • G-protein coupled receptor kinase activity • kinase activity • protein serine/threonine kinase activity • protein binding • alpha-2A adrenergic receptor binding • ATP binding • beta-adrenergic receptor kinase activity Cellular component • cytoplasm • cytosol • membrane • plasma membrane • primary cilium Biological process • G-protein coupled acetylcholine receptor signaling pathway • G-protein coupled receptor signaling pathway • cardiac muscle contraction • phosphorylation • regulation of the force of heart contraction • viral genome replication • negative regulation of striated muscle contraction • positive regulation of catecholamine secretion • receptor internalization • tachykinin receptor signaling pathway • protein phosphorylation • heart development • peptidyl-serine phosphorylation • viral entry into host cell • desensitization of G-protein coupled receptor protein signaling pathway • peptidyl-threonine phosphorylation • negative regulation of the force of heart contraction by chemical signal • signal transduction Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	156	110355
Ensembl	ENSG00000173020	ENSMUSG00000024858
UniProt	P25098	Q99MK8
RefSeq (mRNA)	NM_001619	NM_001290818 NM_130863
RefSeq (protein)	NP_001610.2	NP_001277747.1
Location (UCSC)	Chr 11: 67.27 – 67.29 Mb	Chr 19: 4.29 – 4.31 Mb
PubMed search	[2]	[3]
Wikidata

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Beta adrenergic receptor kinase (also referred to as βARK or BARK) is a serine/threonine intracellular kinase. It is activated by PKA and its target is the beta adrenergic receptor. It is one method by which the cell will desensitize itself from epinephrine overstimulation.^[4][5]

βARK Activation

• (steps 1) Upon stimulation of the Beta adrenergic receptor by epinephrine, Gs will be activated.
• (steps 2 and 3) Gs alpha will then stimulate adenyl cyclase to make cAMP.
• (steps 3 through 6) cAMP will then activate cAMP-dependent kinase (PKA), which, among other proteins that it acts on, will phosphorylate serine and threonine residues on βARK.

Beta Adrenergic Receptor Kinase Activation Pathway.

• (step 7) βARK, itself a serine/threonine kinase, will then phosphorylate serine and threonine residues on the β-adrenergic receptor itself.
• (step 8) This will facilitate Beta-arrestin's binding to the receptor. Additional stimulation by epinephrine will now be unable to activate Gs due to arrestin.

Therefore, βARK is a negative feedback enzyme that will prevent overstimulation of the β-adrenergic receptor.^[4][5]

Other similar systems

In the rhodopsin system, which regulates rod cell function in the retina, rhodopsin kinase will phosphorylate serine and threonine residues on the rhodopsin receptor. Similarly to the βARK system, the phosphorylated rhodopsin residues will then bind to arrestin, resulting in receptor desensitization.

Structure

Protein Structure

The structure of βARK1 consists of a protein of 689 amino acids (79.7 kilodaltons) with a protein kinase catalytic domain that bears greatest sequence similarity to protein kinase C and the cyclic adenosine monophosphate (cyclic AMP)-dependent protein kinase.^[6]

Gene structure

The gene spans approximately 23 kilobases and is composed of 21 exons interrupted by 20 introns. Exon sizes range from 52 bases (exon 7) to over 1200 bases (exon 21), intron sizes from 68 bases (intron L) to 10.8 kilobases (intron A). The splice sites for donor and acceptor were in agreement with the canonical GT/AG rule. Functional regions of beta ARK are described with respect to their location within the exon-intron organization of the gene. Primer extension and RNase protection assays suggest a major transcription start site approximately 246 bases upstream of the start ATG. Sequence analysis of the 5'-flanking/promoter region reveals many features characteristic of mammalian housekeeping genes, i.e. the lack of a TATA box, an absent or nonstandard positioned CAAT box, high GC content, and the presence of Sp1-binding sites. The extraordinarily high GC content of the 5'-flanking region (> 80%) helps define this region as a CpG island that may be a principal regulator of beta ARK expression.^[7]

Interactions

Beta adrenergic receptor kinase has been shown to interact with:

• Beta-gamma complex,^[8]
• G protein
• GIT1,^[9][10]
• GNAQ,^[11]
• PDE6G,^[12]
• PRKCB1^[13] and
• Src.^[12]

See also

• G protein-coupled receptor kinases
• kinase
• G protein

References

1. "Drugs that physically interact with Beta-adrenergic receptor kinase 1 view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. Pippig S, Andexinger S, Daniel K, Puzicha M, Caron MG, Lefkowitz RJ, Lohse MJ (1993). "Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors". J. Biol. Chem. 268 (5): 3201–8. PMID 8381421.
5. Pitcher J, Lohse MJ, Codina J, Caron MG, Lefkowitz RJ (1992). "Desensitization of the isolated beta 2-adrenergic receptor by beta-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase C occurs via distinct molecular mechanisms". Biochemistry. 31 (12): 3193–7. doi:10.1021/bi00127a021. PMID 1348186.
6. Benovic JL, DeBlasi A, Stone WC, Caron MG, Lefkowitz RJ (1989). "Beta-adrenergic receptor kinase: primary structure delineates a multigene family". Science. 246 (4927): 235–40. doi:10.1126/science.2552582. PMID 2552582.
7. Penn RB, Benovic JL (1994). "Structure of the human gene encoding the beta-adrenergic receptor kinase". J. Biol. Chem. 269 (21): 14924–30. PMID 8195124.
8. Raveh A, Cooper A, Guy-David L, Reuveny E (November 2010). "Nonenzymatic rapid control of GIRK channel function by a G protein-coupled receptor kinase". Cell. 143 (5): 750–60. doi:10.1016/j.cell.2010.10.018. PMID 21111235.
9. Premont RT, Claing A, Vitale N, Perry SJ, Lefkowitz RJ (July 2000). "The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing". J. Biol. Chem. 275 (29): 22373–80. doi:10.1074/jbc.275.29.22373. PMID 10896954.
10. Premont RT, Claing A, Vitale N, Freeman JL, Pitcher JA, Patton WA, Moss J, Vaughan M, Lefkowitz RJ (November 1998). "beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein". Proc. Natl. Acad. Sci. U.S.A. 95 (24): 14082–7. doi:10.1073/pnas.95.24.14082. PMC 24330. PMID 9826657.
11. Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB (August 2003). "Differential interaction of GRK2 with members of the G alpha q family". Biochemistry. 42 (30): 9176–84. doi:10.1021/bi034442+. PMID 12885252.
12. Wan KF, Sambi BS, Tate R, Waters C, Pyne NJ (May 2003). "The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth factor". J. Biol. Chem. 278 (20): 18658–63. doi:10.1074/jbc.M212103200. PMID 12624098.
13. Yang XL, Zhang YL, Lai ZS, Xing FY, Liu YH (April 2003). "Pleckstrin homology domain of G protein-coupled receptor kinase-2 binds to PKC and affects the activity of PKC kinase". World J. Gastroenterol. 9 (4): 800–3. PMID 12679936.

External links

• beta-Adrenergic Receptor Kinase at the US National Library of Medicine Medical Subject Headings (MeSH)