respectively. This structure for the βadrenergic receptor is similar to other G-protein-
linked receptors whose cDNAs have been cloned (chapter 2), and is shown in figure 4.8.
Three distinct and pharmacologically important βreceptor subtypes exist:β 1 ,β 2 ,
andβ 3. The genomic organization of the genes encoding the biosynthesis of these three
receptor proteins is somewhat unusual. The β 1 andβ 2 receptor proteins are encoded by
genes lacking introns. (An intron is a region of a gene that tends to be a non-coding
sequence; introns range in size from fewer than 100 nucleotides to over 10,000
nucleotides. Introns differ from coding sequences in that frequently they can be exper-
imentally altered without changing the gene function. Moreover, introns seem to accu-
mulate mutations rapidly during evolution, leading to hypotheses that introns are
composed mainly of “genetic junk”.) The β 3 receptor protein, on the other hand, is
encoded by an intron-containing gene, which provides an opportunity for alternative
splicing as a means of introducing functional heterogeneity into the receptor. Although
each of these receptors is structurally distinct, having varying numbers of amino acids
(β 1 [477 amino acids],β 2 [410], and β 3 [402]), they all exert their final effect by means
of a cAMP secondary messenger.
The three β-adrenoreceptor subtypes have varying localizations and functional prop-
erties. The brain contains both β 1 andβ 2 receptors; the density of β 1 receptors varies in
different brain areas to a much greater extent than does that of β 2 receptors.β 1 recep-
tors predominate in the cerebral cortex; β 2 receptors are more common in the cerebel-
lum. Likewise, there is a coexistence of β 1 andβ 2 receptors in the heart, with both
receptor subtypes being coupled to the electrophysiological effects of catecholamines
upon the myocardium. β 2 receptors tend to predominate in the lung.
Theβ 3 receptor is distinct from the β 1 orβ 2 receptor. In humans, the β 3 receptor is
linked to obesity, diabetes, and control of lipid metabolism. mRNA for β 3 receptors is
selectively expressed in brown adipose tissue in newborn humans. Polymorphism
is common within the structure of the β 3 receptor. A Trp64Arg point mutation in the β 3
224 MEDICINAL CHEMISTRY
Figure 4.8 Schematic structure of the mammalian β 2 -adrenergic receptor. There are seven
membrane-spanning helical regions composed of hydrophobic amino acid sequences, and at least
two glutamine-linked glycosylation sites near the N-terminal. P shows potential sites of phospho-
rylation by cAMP-linked protein kinase; arrows indicate serine and threonine molecules that can
be the site of regulatory phosphorylation by receptor kinase.