5-HT receptor subtypes
Current knowledge of 5-HT receptors has been derived from advances in
medicinal chemistry, from the synthesis of ligands that show considerable
specificity for subpopulations of 5-HT receptors. The application of such
ligands to our understanding of the distribution of the 5-HT receptor
subtypes has been largely due to quantitative in vitro autoradiographic
techniques and the application of such imaging techniques as positron
emission tomography. Functional studies undoubtedly lag behind but the
development of sophisticated electrophysiological techniques and studies
of changes in secondary messenger systems which respond to the binding
of selective ligands to the 5-HT receptor subtypes have opened up the
probability that the physiological importance of the numerous receptor
subtypes will soon be clarified.
As a consequence of the application of these various techniques, the
International Union of Pharmacological Societies (IUPHAR) Commission
on serotonin nomenclature has published two major reports which attempt
to classify the various receptor subtypes according to their ligand binding
properties and secondary messenger systems. The first report classified
5-HT receptors into 5-HT1-like (comprising 5-HT1A, 1B, 1C and 1D), 5-HT2
(formerly the 5-HT-D receptor) and 5-HT2 (formerly the 5-HT-M receptor).
The detection of a novel 5-HT receptor, that could not be classified as 5-HT1,
5-HT2 or 5-HT3, in both the peripheral and central nervous systems,
extended the receptor types to 5-HT4. The application of molecular biology
techniques has led to the cloning and sequencing of at least six different
5-HT receptors, namely 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3.
Further studies of the second messenger systems to which these receptor
subtypes are attached have shown that the 5-HT1-like, 5-HT2 and 5-HT4 receptors belong to the G protein coupled receptor superfamily, whereas
the 5-HT3 receptor belongs to the same family as the nicotinic, gammaaminobutyric
acid-A (GABA-A) and glycine receptors which are ion gated
channel receptors.
The most recent publication of the IUPHAR Commission has redefined
the 5-HT receptor subtypes according to their second messenger
associations and thereby helped to stress the functional role of the receptor
subtypes rather than relying primarily on the specificities of ligands that
bind to them. This approach has led to the classification of 5-HT receptors
into those linked to adenylate cyclase (5-HT1A, 5-HT1B, 5-HT1D, 5-HT4),
those linked to the phosphatidyl inositol system (5-HT2A, 5-HT2B and
5-HT2C), and those linked directly to ion channels (5-HT3). Table 6.1
summarizes the accepted classification of the 5-HT receptor subtypes, all of
which occur in the brain, together with the most specific agonists and
antagonists which have been developed. The structures of the seven
subtypes of the serotonin receptor have now been determined. Apart from
the ionotropic 5-HT3 receptors (Figure 6.2), the other receptors are of the
metabotropic type (Figure 6.3, 5-HT2 receptor). Figure 6.4 illustrates the
molecular structure of the 5-HT4 receptor.
More recently, the family of 5-HT receptors has been dramatically
increased to include 5-HT4, 5-HT5A and 5-HT5B, 5-HT6 and 5-HT7. The
5-HT6 and 5-HT7 receptors are positively linked to adenylate cyclase. Of
these, only the 5-HT4 receptor has so far not been cloned. Of these newly
discovered receptors, only the 5-HT4 receptor has been investigated in some
detail. This receptor is quite widely distributed in the brain and peripheral
tissues where they are positively coupled to adenylate cyclase. In the brain,
the 5-HT4 receptors facilitate acetylcholine release and may play a role in
peristalsis. It has been hypothesized that in the brain 5-HT4 receptors may
also play a role in facilitating cholinergic transmission and thereby have a
potential role to play in preventing cognitive deficits which are associated
with cortical cholinergic malfunction. The possible clinical significance of
5-HT4 receptors must await the development of specific agonists and
antagonists. So far, such compounds have not been developed. Figures 6.5,
6.6 and 6.7 illustrate the distribution of 5-HT3, 5-HT4, 5-HT6 and 5-HT7
receptors in the human brain.
Despite the dramatic advances which have taken place in the
identification and characterization of 5-HT receptor subtypes, it is evident
that many of the ligands used to characterize these receptor subtypes are
not completely selective. It must also be emphasized that receptors are the
products of genes and are therefore subject to genetic changes and, as a
consequence, variability in physiological and pharmacological responsiveness.
Thus affinity, potency and intrinsic activity of a drug at one receptor
may vary depending on the time, species and receptor–effector coupling. It is already known, for example, that ipsapirone, buspirone, spiroxatrine and
lysergic acid diethylamide (LSD) may behave either as agonists or
antagonists depending on the functional model being used to assess their
activity. A similar problem arises with intrinsic activity which is usually
assumed to be a direct reflection of the pharmacological properties of the
drug. It seems possible that the affinity can also be influenced by the nature
of the genetically determined receptor–effector coupling and is therefore
tissue (and species) dependent. Such factors may help to explain why the
identification and subclassification of 5-HT receptor subtypes is complex
and often confusing.
This dilemma can be illustrated by the attempts being made to identify
the functional role of 5-HT receptor subtypes using ligands which are
believed to be specific in their binding properties. Such ligands may prove
to be non-selective, more selective for an as yet unidentified 5-HT receptor
subtype or more selective for a non-5-HT receptor site. Conversely several
non-5-HT ligands are known to bind to 5-HT receptors with a high affinity.
For example, the alpha1 adrenoceptor antagonist WB4101, and the beta
adrenoceptor antagonist pindolol, have a high affinity to 5-HT1A receptors.
Current knowledge of 5-HT receptors has been derived from advances in
medicinal chemistry, from the synthesis of ligands that show considerable
specificity for subpopulations of 5-HT receptors. The application of such
ligands to our understanding of the distribution of the 5-HT receptor
subtypes has been largely due to quantitative in vitro autoradiographic
techniques and the application of such imaging techniques as positron
emission tomography. Functional studies undoubtedly lag behind but the
development of sophisticated electrophysiological techniques and studies
of changes in secondary messenger systems which respond to the binding
of selective ligands to the 5-HT receptor subtypes have opened up the
probability that the physiological importance of the numerous receptor
subtypes will soon be clarified.
As a consequence of the application of these various techniques, the
International Union of Pharmacological Societies (IUPHAR) Commission
on serotonin nomenclature has published two major reports which attempt
to classify the various receptor subtypes according to their ligand binding
properties and secondary messenger systems. The first report classified
5-HT receptors into 5-HT1-like (comprising 5-HT1A, 1B, 1C and 1D), 5-HT2
(formerly the 5-HT-D receptor) and 5-HT2 (formerly the 5-HT-M receptor).
The detection of a novel 5-HT receptor, that could not be classified as 5-HT1,
5-HT2 or 5-HT3, in both the peripheral and central nervous systems,
extended the receptor types to 5-HT4. The application of molecular biology
techniques has led to the cloning and sequencing of at least six different
5-HT receptors, namely 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3.
Further studies of the second messenger systems to which these receptor
subtypes are attached have shown that the 5-HT1-like, 5-HT2 and 5-HT4 receptors belong to the G protein coupled receptor superfamily, whereas
the 5-HT3 receptor belongs to the same family as the nicotinic, gammaaminobutyric
acid-A (GABA-A) and glycine receptors which are ion gated
channel receptors.
The most recent publication of the IUPHAR Commission has redefined
the 5-HT receptor subtypes according to their second messenger
associations and thereby helped to stress the functional role of the receptor
subtypes rather than relying primarily on the specificities of ligands that
bind to them. This approach has led to the classification of 5-HT receptors
into those linked to adenylate cyclase (5-HT1A, 5-HT1B, 5-HT1D, 5-HT4),
those linked to the phosphatidyl inositol system (5-HT2A, 5-HT2B and
5-HT2C), and those linked directly to ion channels (5-HT3). Table 6.1
summarizes the accepted classification of the 5-HT receptor subtypes, all of
which occur in the brain, together with the most specific agonists and
antagonists which have been developed. The structures of the seven
subtypes of the serotonin receptor have now been determined. Apart from
the ionotropic 5-HT3 receptors (Figure 6.2), the other receptors are of the
metabotropic type (Figure 6.3, 5-HT2 receptor). Figure 6.4 illustrates the
molecular structure of the 5-HT4 receptor.
More recently, the family of 5-HT receptors has been dramatically
increased to include 5-HT4, 5-HT5A and 5-HT5B, 5-HT6 and 5-HT7. The
5-HT6 and 5-HT7 receptors are positively linked to adenylate cyclase. Of
these, only the 5-HT4 receptor has so far not been cloned. Of these newly
discovered receptors, only the 5-HT4 receptor has been investigated in some
detail. This receptor is quite widely distributed in the brain and peripheral
tissues where they are positively coupled to adenylate cyclase. In the brain,
the 5-HT4 receptors facilitate acetylcholine release and may play a role in
peristalsis. It has been hypothesized that in the brain 5-HT4 receptors may
also play a role in facilitating cholinergic transmission and thereby have a
potential role to play in preventing cognitive deficits which are associated
with cortical cholinergic malfunction. The possible clinical significance of
5-HT4 receptors must await the development of specific agonists and
antagonists. So far, such compounds have not been developed. Figures 6.5,
6.6 and 6.7 illustrate the distribution of 5-HT3, 5-HT4, 5-HT6 and 5-HT7
receptors in the human brain.
Despite the dramatic advances which have taken place in the
identification and characterization of 5-HT receptor subtypes, it is evident
that many of the ligands used to characterize these receptor subtypes are
not completely selective. It must also be emphasized that receptors are the
products of genes and are therefore subject to genetic changes and, as a
consequence, variability in physiological and pharmacological responsiveness.
Thus affinity, potency and intrinsic activity of a drug at one receptor
may vary depending on the time, species and receptor–effector coupling. It is already known, for example, that ipsapirone, buspirone, spiroxatrine and
lysergic acid diethylamide (LSD) may behave either as agonists or
antagonists depending on the functional model being used to assess their
activity. A similar problem arises with intrinsic activity which is usually
assumed to be a direct reflection of the pharmacological properties of the
drug. It seems possible that the affinity can also be influenced by the nature
of the genetically determined receptor–effector coupling and is therefore
tissue (and species) dependent. Such factors may help to explain why the
identification and subclassification of 5-HT receptor subtypes is complex
and often confusing.
This dilemma can be illustrated by the attempts being made to identify
the functional role of 5-HT receptor subtypes using ligands which are
believed to be specific in their binding properties. Such ligands may prove
to be non-selective, more selective for an as yet unidentified 5-HT receptor
subtype or more selective for a non-5-HT receptor site. Conversely several
non-5-HT ligands are known to bind to 5-HT receptors with a high affinity.
For example, the alpha1 adrenoceptor antagonist WB4101, and the beta
adrenoceptor antagonist pindolol, have a high affinity to 5-HT1A receptors.
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