Beta adrenergic receptor kinase

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

βARK Activation

 * (steps 1) Upon stimulation of the Beta adrenergic receptor by is_associated_with::epinephrine, Gs will be activated.


 * (steps 2 and 3) Gs alpha will then stimulate is_associated_with::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.




 * (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-is_associated_with::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.

Other similar systems
In the is_associated_with::rhodopsin system, which regulates is_associated_with::rod cell function in the is_associated_with::retina, is_associated_with::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.

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.

Gene structure
The is_associated_with::gene spans approximately 23 kilobases and is composed of 21 is_associated_with::exons interrupted by 20 is_associated_with::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 is_associated_with::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 is_associated_with::housekeeping genes, i.e. the lack of a is_associated_with::TATA box, an absent or nonstandard positioned is_associated_with::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.

Interactions
Beta adrenergic receptor kinase has been shown to interact with:


 * is_associated_with::Beta-gamma complex,
 * is_associated_with::G protein
 * is_associated_with::GIT1,
 * is_associated_with::GNAQ,
 * is_associated_with::PDE6G,
 * is_associated_with::PRKCB1 and
 * Src.