Neuroscience
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Cellular and Molecular Neurobiology
12. Biogenic Amine Neurotransmitters
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Neuroscience
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Cellular and Molecular Neurobiology
12. Biogenic Amine Neurotransmitters
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The receptors for NE and E were originally classified based on the observation that some physiological actions were mimicked by the catecholamine analog, isoproterenol, whereas others were not. This observation led to the convention that actions that could be mimicked by isoproterenol were classified as mediated by b-receptors. Those actions that were not mimicked by isoproterenol were classified as mediated by a-receptors.
This classification has since been extended to include subclasses of a
and ß receptors based on the capacity of drugs to selectively activate
(or block) specific physiological responses to NE and E. The molecular cloning
of mRNAs for distinct subclasses of NE and E receptors also aided in the classification
of receptors. Tables I, II and III summarize autonomic and CNS NE and E receptor
types, their location and their physiological action. Noteworthy is the fact
that most a receptor responses are excitatory, while
most b responses
are inhibitory (although some exceptions exist, e.g. cardiac muscle). Also,
the a receptor is invariably linked to IP3
production, whereas the b receptor is associated
with increased levels of cAMP.
The distribution of NE receptors in the CNS is complex and not yet well resolved.
Generally, both a and b
receptors are believed to be modulators of the
actions of other neurotransmitters. As summarized in Table III, a1
receptors are often excitatory, acting via IP3.
In contrast, a2 receptors are inhibitory
acting via decreased levels of cAMP. b receptors
are inhibitory and act through increased levels of cAMP (TABLE II). The anatomical
location of the specific receptor subtypes is not yet clearly delineated.
In the CNS, dopamine receptors, designated by the letter D, are grouped into two large families based on cDNA-derived structural similarities, synaptic action and signaling mechanism (TABLE III). The D1 family (D1 and D5) increases cAMP level, and has a negative influence on the excitability of its target cell. The D2 family (D2, D3, and D4) decreases cAMP level and increases the excitability of the target cell. As shown in Table II the two families of receptors appear to have similar anatomical distributions. However, this may be misleading. Future research will probably show that the location of the receptors is on distinct postsynaptic cells or on presynaptic versus postsynaptic sites.
Two classes of 5-HT receptors, 5-HT1B and 5-HT1D, appear to predominantly act as autoreceptors to modulate the synthesis and release of 5-HT from the presynaptic terminal of serotonergic neurons. Other receptor types lead to an increase in the excitability of the target cell (5-HT2 and 5-HT4), while still others (5-HT1) decrease excitability. Interestingly, receptors that mediate increased excitability do so through at least three mechanisms, PLCbstimulation, stimulation of adenylyl cyclase or the direct interaction of 5-HT with the ion channel to depolarize the membrane.
Three subtypes of histamine receptors have been identified. All three are G protein linked and all three are present in the CNS as well as the periphery. Thus far, only peripheral H receptors have been characterized (See Table V).
H1 receptors mediate the well-known physiological responses to histamine that occur in response to histamine liberation from mast cells. A large number of prescription and over the counter drugs, antihistamines, act by blocking H1 receptors. Because most H1 blockers also have a sedative effect and cause drowsiness, it appears likely that H1 receptors are also present in the CNS. Recently developed H1 blockers that do not cross that blood brain barrier have circumvented the sedative problem.
The mechanism of action of H1 receptors is the activation of PLCb
H2 receptors are responsible for the peripheral actions of histamine that are not blocked by H1 antagonists. These receptors are coupled to stimulation of cAMP and are responsible for histamine's stimulation of gastric acid secretion. Recently developed specific H2 receptor blockers, Tagamet and Zantac, are effective clinically for excess secretion of gastric acid. Because these drugs do not cross the blood brain barrier, they have no effects on the CNS.
H3 histamine receptors are found on histamine
nerve terminals where they regulate the release of histamine. There is evidence
for these receptors on the terminals of other neurotransmitter types as well,
indicating that histamine may regulate the synthesis and secretion of other
neurotransmitters. When presynaptic receptors are located on cells other than
their own neurotransmitter type they are called heteroreceptors.
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Contact the author(s) at: nba_course@uth.tmc.edu
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The University of Texas Health Science Center at Houston
Created through the Multimedial Scriptorium - Academic Technology
