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Beta adrenergic receptor kinase (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.[1][2]
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BARK 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, it will phosphorylate serine and threonine residues on BARK.
- (step 7) BARK, itself a serine/threonine kinase, will then phosphorylate serine and threonine resides on the B-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, BARK is a negative feedback enzyme which will prevent over stimulation of the B-adrenergic receptor.[1][2]
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 BARK system, the phosphorylated rhodopsin residues will then bind to arrestin resulting in receptor desensitization.
Structure
Protein Structure
The structure of BARK1 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. [3]
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. [4]
See also
References
- ^ a b Pippig S, et al. Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors. J Biol Chem. 1993 Feb 15;268(5):3201-8.
- ^ a b Pitcher, J, et al. 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. 1992 Mar 31;31(12):3193-7.
- ^ Benovic, JL, et al. Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science, Vol 246, Issue 4927, 235-240. 1989.
- ^ Benovic, JL, et al. Structure of the human gene encoding the beta-adrenergic receptor kinase. J Biol Chem. 1994 May 27;269(21):14924-30
External links
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