norepinephrine > isoproterenol. The β receptors are usually inhibitory on smooth
muscle but stimulate the myocardium. Their drug sensitivity is: isoproterenol >
epinephrine > norepinephrine. None of these receptors is truly tissue specific, and many
organs contain both α and β adrenoceptors, although usually one type predominates.
Studies using radiolabeled agonists and antagonists have identified α receptors in
both brain and peripheral tissues and have demonstrated that the binding properties
are essentially the same in both of these locations. Early pharmacological and physiological studies supported the existence of two types of α receptor (α 1 , α 2 ). These
two basic types have varying anatomical and histological localizations. Some tissues
possess only α 1 receptors, some possess only α 2 receptors and some possess mixtures
of both. The brain, for example, contains proportions of both α 1 and α 2 receptors with
highly variable distributions in different brain regions. The primary amino acid
sequences of both the α 1 and α 2 receptors have been determined. The sequences of these
two α receptors are not more closely related to each other than either is to any of the
three proteins that make up the β-adrenergic receptor family. Not surprisingly, the α
adrenergic receptors share marked structural similarities with dopamine receptors
(discussed in detail in section 4.4.1) and with other members of the G-protein-linked
receptor family (section 2.9).
Recent cloning and sequence analysis studies suggest that there are three subtypes of
α 1 receptors and three subtypes of α 2 receptors. The three subtypes of the α 1 receptor
have been designated α 1A, α 1B , and α 1D , and tend to be differentially distributed in the
kidney, liver, and aorta, respectively. Cloning studies reveal that each arises from a different chromosome and each contains a different number of amino acids: α 1A [466
amino acids], α 1B [515], α 1D [560]. Similarly, there are three subtypes of α 2 receptors,
designated α 2A , α 2B , and α 2C . As with the α 1 -receptor subtypes, each α 2 receptor is
encoded on a different chromosome and contains a varying number of amino acids: α 2A
[450 amino acids], α 2B [450], α 2C [461]. The α 1B receptor has been shown to activate
phosphoinositide-specific phospholipase C (PI-PLC), resulting in liberation of diacylglycerol (DAG) and inositol triphosphate (IP 3 ), while the α 1D receptor has been linked
to activation of Ca
2+ channels. All three of the known subtypes of the α 2 receptor are
linked to inhibition of adenylyl cyclase activity. As with other receptors linked to inhibition of adenylyl cyclase, these receptors have relatively short C-terminal tails.
4.3.4 Adrenergic Receptors: The β Receptor Family
Hydropathicity analyses of the β-adrenergic receptor suggests that it possesses seven
membrane-spanning hydrophobic regions (I–VII), each 20–24 amino acids in length. In
addition, there is a long intracellular C-terminal hydrophilic sequence, a shorter extracellular N-terminal hydrophilic sequence, and a long cytoplasmic loop between transmembrane segments V and VI. Numerous sites accessible to phosphorylation are
located on the C-terminal portion of the protein, while sites for N-glycosylation are on
the N-terminal extracellular segment. The transmembrane hydrophobic helices are
involved in the formation of the catecholamine binding site, and residues in the
C-terminal sequence seemingly play a role in the interaction between the receptor and
GTP-binding proteins. Finally, an aspartate in transmembrane segment III and two serines in segment V are believed to interact with the amino and catechol hydroxyl groups,
NEUROTRANSMITTERS AND THEIR RECEPTORS
223
muscle but stimulate the myocardium. Their drug sensitivity is: isoproterenol >
epinephrine > norepinephrine. None of these receptors is truly tissue specific, and many
organs contain both α and β adrenoceptors, although usually one type predominates.
Studies using radiolabeled agonists and antagonists have identified α receptors in
both brain and peripheral tissues and have demonstrated that the binding properties
are essentially the same in both of these locations. Early pharmacological and physiological studies supported the existence of two types of α receptor (α 1 , α 2 ). These
two basic types have varying anatomical and histological localizations. Some tissues
possess only α 1 receptors, some possess only α 2 receptors and some possess mixtures
of both. The brain, for example, contains proportions of both α 1 and α 2 receptors with
highly variable distributions in different brain regions. The primary amino acid
sequences of both the α 1 and α 2 receptors have been determined. The sequences of these
two α receptors are not more closely related to each other than either is to any of the
three proteins that make up the β-adrenergic receptor family. Not surprisingly, the α
adrenergic receptors share marked structural similarities with dopamine receptors
(discussed in detail in section 4.4.1) and with other members of the G-protein-linked
receptor family (section 2.9).
Recent cloning and sequence analysis studies suggest that there are three subtypes of
α 1 receptors and three subtypes of α 2 receptors. The three subtypes of the α 1 receptor
have been designated α 1A, α 1B , and α 1D , and tend to be differentially distributed in the
kidney, liver, and aorta, respectively. Cloning studies reveal that each arises from a different chromosome and each contains a different number of amino acids: α 1A [466
amino acids], α 1B [515], α 1D [560]. Similarly, there are three subtypes of α 2 receptors,
designated α 2A , α 2B , and α 2C . As with the α 1 -receptor subtypes, each α 2 receptor is
encoded on a different chromosome and contains a varying number of amino acids: α 2A
[450 amino acids], α 2B [450], α 2C [461]. The α 1B receptor has been shown to activate
phosphoinositide-specific phospholipase C (PI-PLC), resulting in liberation of diacylglycerol (DAG) and inositol triphosphate (IP 3 ), while the α 1D receptor has been linked
to activation of Ca
2+ channels. All three of the known subtypes of the α 2 receptor are
linked to inhibition of adenylyl cyclase activity. As with other receptors linked to inhibition of adenylyl cyclase, these receptors have relatively short C-terminal tails.
4.3.4 Adrenergic Receptors: The β Receptor Family
Hydropathicity analyses of the β-adrenergic receptor suggests that it possesses seven
membrane-spanning hydrophobic regions (I–VII), each 20–24 amino acids in length. In
addition, there is a long intracellular C-terminal hydrophilic sequence, a shorter extracellular N-terminal hydrophilic sequence, and a long cytoplasmic loop between transmembrane segments V and VI. Numerous sites accessible to phosphorylation are
located on the C-terminal portion of the protein, while sites for N-glycosylation are on
the N-terminal extracellular segment. The transmembrane hydrophobic helices are
involved in the formation of the catecholamine binding site, and residues in the
C-terminal sequence seemingly play a role in the interaction between the receptor and
GTP-binding proteins. Finally, an aspartate in transmembrane segment III and two serines in segment V are believed to interact with the amino and catechol hydroxyl groups,
NEUROTRANSMITTERS AND THEIR RECEPTORS
223