| Anatomy | Cell Biology | Physiology and Behavior | Clinical |
Properties of Monoamine Receptors
The vast majority of the MA receptors are seven transmembrane, G-protein coupled receptors (GPCR) that mediate MA action through one of a few mechanisms. These are the same mechanisms employed by other GPCR, such as the muscarinic receptors (Chapter 12, Part 5) and GPC-glutamate receptors (Chapter 13, Part 3). These mechanisms are:
- Stimulation or inhibition of adenylyl cyclase (Click here to see mechanism),
- Stimulation of PLCβ or PLA (Click here to see mechanism), and
- Direct action on ion channel (Click here to see mechanism).
As will be described below, one type of MA receptor, 5-HT3, is unusual in that it is NOT LINKED TO G PROTEIN LINKED RECEPTORS. Instead, 5-HT3 receptors are ligand gated ion channels, similar in structure and function to ionotripic nicotinic cholinergic receptors and glutamate receptors.
NE and E Receptors
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 β-receptors. Those actions that were not mimicked by isoproterenol were classified as mediated by α-receptors.
Relationship Between Peripheral NE and E Receptor Type, Location and Effector Mechanism
This classification has since been extended to include subclasses of α and β 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 α receptor responses are excitatory, while most β responses are inhibitory (although some exceptions exist, e.g. cardiac muscle). Also, the α receptor is invariably linked to IP3 production, whereas the β receptor is associated with increased levels of cAMP.
Relationship Between CNS NE Receptor Type and Effector Mechanism
The distribution of NE receptors in the CNS is complex and not yet well resolved. Generally, both α and β receptors are believed to be modulators of the actions of other neurotransmitters. As summarized in Table II, α1 receptors are often excitatory, acting via IP3. In contrast, α2 receptors are inhibitory acting via decreased levels of cAMP. β 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.
DA Receptors
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 III 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.
Relationship Between CNS Dopamine Receptor Type, Location, and Effector Mechanism
5-HT Receptors
All but one of the 5-HT receptors belongs to the G protein coupled receptor superfamily. The one exception is the 5-HT3 receptor, which is a ligand gated ion channel. As is apparent from the summary in Table IV, 5-HT mediated actions occur through the same types of second messenger mechanisms as cholinergic and catecholamine G protein linked receptors.
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, PLCβ stimulation, stimulation of adenylyl cyclase or the direct interaction of 5-HT with the ion channel to depolarize the membrane.
Relationship Between CNS 5-HT Receptor Type and Effector Mechanism
Histamine Receptors
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).
Relationship Between CNS and Peripheral Histamine Receptor Type, Location and Effector Mechanism
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 PLCβ
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.
