respectively. This structure for the β adrenergic receptor is similar to other G-proteinlinked receptors whose cDNAs have been cloned (chapter 2), and is shown in figure 4.8.
Three distinct and pharmacologically important β receptor subtypes exist: β 1 , β 2 ,
and β 3 . The genomic organization of the genes encoding the biosynthesis of these three
receptor proteins is somewhat unusual. The β 1 and β 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 experimentally altered without changing the gene function. Moreover, introns seem to accumulate 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 properties. The brain contains both β 1 and β 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 receptors predominate in the cerebral cortex; β 2 receptors are more common in the cerebellum. Likewise, there is a coexistence of β 1 and β 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.
The β 3 receptor is distinct from the β 1 or β 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 phosphorylation by cAMP-linked protein kinase; arrows indicate serine and threonine molecules that can
be the site of regulatory phosphorylation by receptor kinase.
Three distinct and pharmacologically important β receptor subtypes exist: β 1 , β 2 ,
and β 3 . The genomic organization of the genes encoding the biosynthesis of these three
receptor proteins is somewhat unusual. The β 1 and β 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 experimentally altered without changing the gene function. Moreover, introns seem to accumulate 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 properties. The brain contains both β 1 and β 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 receptors predominate in the cerebral cortex; β 2 receptors are more common in the cerebellum. Likewise, there is a coexistence of β 1 and β 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.
The β 3 receptor is distinct from the β 1 or β 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 phosphorylation by cAMP-linked protein kinase; arrows indicate serine and threonine molecules that can
be the site of regulatory phosphorylation by receptor kinase.