Genetics of the Receptor: Receptor Codon, Codon Mutations

The importance of the genetic background for blood pressure has been studied extensively. FEINLEIB [54] and ZIMMER [55] suppose that about 60% of blood pressure variance of adults is genetically determined. This big influence of genetics can easily be seen by comparing blood pressure of relatives. The correlation is highest for monozygotic twins and falls with decreasing genetic similarity.

Adrenergic receptors are members of the G protein family (see section gprotein). They possess seven regions of 20 to 24 hydrophobic amino acids crossing the membrane in -helixes[56]. Their amino acid homologies are strongest for these membrane spanning domains . The aminoterminus contains two sites for asparagine-linked glycosylation.   With the help of deleted mutants of the 2ar [57, 58] it has been shown that glycosylation deficient mutants do not change their agonist binding characteristics[59, 60] nor in the signal transduction, as binding to the G protein and stimulating the adenylate cyclase (see page ), whereas the density of receptors is significantly reduced. The glycosylation  therefore plays a major role in the translocation of the receptor to the plasma membrane. The binding site for agonists and antagonists     results from interaction of the catecholamine group with the carboxylic group of Asp-113 in the 3 hydrophobic domain of the receptor[61, 62, 63, 64, 65]. Agonistic effects are induced by hydrogen bonds of the hydroxy groups of Ser-204 and Ser-207 and the meta- or para-hydroxy groups of the ligand.

For stabilizing the binding box, cysteines in extracellular loops are essential. When Cys-106 and Cys-184 are substituted for valine, the ligand binding strength is dramatically reduced [33, 26]. Amino acid substitutions of the membrane domains MI, MII, MIII and MVII also decrease the ligand binding affinity. After glycosylation , the 2ar is also modified by palmitoylisation  at Cys-341 (N-terminal domain). This posttranslational modification is, as shown by deleted mutants[66], crucial for the interaction with the G protein.  

The gene of the human 2ar has been localized to chromosome 5q31-q32 (see table genloci)[67]. The gene is intronless throughout[68]. Its promoter  region contains a variety of binding sites for regulatory elements, including a steroid receptor binding hexamer (TGTTCT)[68, 69], cyclic AMP responsive elements[70], a consensus TATA box and a consensus CAAT box[68]. Interestingly, a non-overlapping cistron in the receptor mRNA  5' leader region is translated and the resulting peptide inhibits receptor translation[71]. Despite the vast amount of literature on the molecular biology, structure and function of the human adrenergic receptor, little is known about the existence of alleles .

There was shown by LIGGETT[72], that substitution of an extracellular cysteine enhances receptor phosphorylation and desensitization. He[73] and others[74, 75] have shown, using site-directed mutagenesis, that mutations involving small regions of the 2ar, including changes of a single amino acid, can markedly alter the functional properties of the receptor.

2ar cDNA was sequenced by several groups[76, 77, 78]. The derived sequence consists of 413 amino acids.