Cardiovascular disorders

Hypertension; Essential hypertension; Aortic coarctation

Hypertension is a cardiovasculature disease characterized by high blood pressure. Essential hypertension, also called idiopathic hypertension, is hypertension that does not have an identifiable cause, which accounts for ~95% of all reported cases. Aortic coarctation, also called aortic narrowing, is a congenital cardiovascular disease characterized by the constriction of the aorta in the area where the ductus arteriosis inserts. As a result of this narrowing, the left ventricle must generate higher pressure to achieve the same flow of blood out of the heart, thus causing stress to the heart muscles. In extreme cases, the heart cannot push enough blood through the narrowing resulting in the lack of blood delivery to the lower half of the body. Mutations in GRK4 have been linked to hypertension. In general, GRKs are associated with both genetic and acquired hypertension as they function to desensitize G protein-coupled receptors, including D1 receptors (dopamine receptors). D1 receptors that are phosphorylated at basal levels on serine residues of the protein are expressed at higher levels in the renal proximal tubules in rodent models of hypertension and in human patients with hypertension, indicating a role for dopamine signalling in the development of hypertension. Additionally, single nucleotide polymorphisms (SNPs) in the GRK4-gamma subunit were observed in human patients with essential hypertension which were associated with increased GRK4 catalytic activity, resulting in elevated levels of serine phosphorylation of the D1 protein and the uncoupling of the D1 receptor from its G protein effector complex in the renal proximal tubule.
 

GRK4 appears to be a tumour requiring protein (TRP), since it undergoes much fewer mutations than the typical protein in cancer cells.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in human Prostate cancer - primary (%CFC= +65, p<0.009). The COSMIC website notes an up-regulated expression score for GRK4 in diverse human cancers of 366, which is 0.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 50 for this protein kinase in human cancers was 0.8-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0 % in 24900 diverse cancer specimens. This rate is -98 % lower than the average rate of 0.075 % calculated for human protein kinases in general. Such a very low frequency of mutation in human cancers is consistent with this protein kinase playing a role as a tumour requiring protein (TRP).

Highest percent mutation rates per 100 amino acids length in human cancers: 0.02 % in 942 upper aerodigestive tract cancers tested; 0.01 % in 1822 lung cancers tested.

None > 1 in 20,183 cancer specimens

No deletions, insertions or complex mutations are noted on the COSMIC website.