Structure of Receptors betaAdrenergic Receptor

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20.10— Structure of Receptors:
b ­Adrenergic Receptor
Structures of receptors are conveniently discussed in terms of functional domains. Consequently, for membrane receptors there will be functional ligand­binding domains and the transmembrane domains, which for many membrane receptors involve protein kinase activities. In addition, specific immuno­logical domains contain primary epitopes of antigenic regions. Several membrane receptors have been cloned and studied with regard to structure and function, including the b receptors ( 1 and 2), which recognize catecholamines, principally norepinephrine, and stimulate adenylate cyclase. The 1 and 2 receptors are subtypes that differ in affinities for norepinephrine and for synthetic antagonists. Thus 1­adrenergic receptor binds norepinephrine with a higher affinity than epinephrine, whereas the order of affinities is reversed for the 2­adrenergic receptor. The drug isoproterenol has a greater affinity for both receptors than the two hormones. In Figure 20.31 the amino acid sequence is shown (with single letter abbreviations for amino acids; see Table 20.4 for list) for the 2­adrenergic receptor. A polypeptide stretch extending from a
helix I extends to the extracellular space. There are seven membrane­spanning domains and these appear also in the 1 receptor, where there is extensive homology with the 2 receptor. Cytosolic peptide regions extend to form loops between I and II, III and IV, and V and VI and an extended chain from VII.
Figure 20.31 Proposed model for insertion of the b 2­adrenergic receptor (AR) in the cell membrane. The model is based on hydropathicity analysis of the human 2­AR. Standard one­letter codes for amino acid residues are used. Hydrophobic domains are represented as transmembrane helices. Pink circles with black letters indicate residues in the human sequence that differ from those in hamster. Also noted are the potential sites of N­linked glycosylation. Redrawn from Kobilka, B. K., Dixon, R. A., Frielle, T., Dohlman, H. G., et al. Proc. Natl. Acad. Sci. USA 84:46, 1987.