Receptors for neurotransmitters

There are two major types of receptor which are activated by neurotransmitters. These are the ionotropic and metabotropic receptors. The former receptor type is illustrated by the amino acid neurotransmitter receptors for glutamate, gamma-aminobutyric acid (GABA) and glycine, and the acetylcholine receptors of the nicotinic type. These are examples of fast transmitters in that they rapidly open and close the ionic channels in... 

In the last decade, considerable evidence has emerged that certain steroids may alter neuronal excitability via their action at the cell surface through interaction with certain neurotransmitter receptors. For steroids with these particular properties, the term neuroactive steroids has been used (Majewska et al. 1986 Paul and Purdy 1992 Rupprecht and Holsboer 1999). 

For pharmacodynamic agents acting within one species (human), selectivity may also be achieved by differences in accumulation, when similar receptors are located in cells or in membranes of different character. The neurotransmitter receptors, for example, are similar, but are found in a variety of highly differentiated cells whose membranes are unlikely to possess the same physical characteristics. 

Figure 7.5. Structures of some neurotransmitters. Receptors for all of these are targets of drags in current use.

Part of a flawless proof of solubilization is gel filtration and the density gradient. The proof is by no means trivial. At the end of the 1980s, a half-dozen papers were published by different laboratories that aU claimed they had solubilized the neurotransmitter receptor for NMDA in native form with deoxycholate, TRITON, or cholate. The centrifugation criterion was given as the only proof. However, the NMDA receptor does not even go in solution with deoxycholate. 

Elucidation of the stmctural requirements for dmg interaction at the recognition site is by the study of stmcture—activity relationships (SAR), in which, according to a specific biologic response, the effects of systematic molecular modification of a parent dmg stmcture are determined. Such studies have permitted the classification of discrete classes of pharmacological receptors. For example, the neurotransmitter acetylcholine acts at both peripheral and central receptors which are of at least three distinct types. The effects of acetylcholine are mimicked in smooth and cardiac muscles and secretory... 

The G-proteins are heterotrimers made of three families of subunits, a, P, and y, which can interact specifically with discrete regions on G-protein-coupled receptors. This includes most receptors for neurotransmitters and polypeptide hormones (see Neuroregulators). G-protein-coupled receptors also embrace the odorant receptor family and the rhodopsin-linked visual cascade. 

Of the several classes of receptors for endogenous chemical signals [3], two are used as postsynaptic receptors in synaptic transmission ligand-gated ion channels (LGICs) and G protein-coupled receptors (GPCRs Fig. 1). Due to the large number of transmitters and the existence of several receptor types for almost all, postsynaptic receptor activation is the most diversified step of synaptic transmission. Table 1 shows selected neurotransmitter receptors. 

In the light of such considerations, it is possible to discuss toxins which have already been analyzed in terms of their sites of action. Such a discussion is best conducted by categorizing the various possible cellular sites at which a toxin might act. The most obvious sites are the membrane channels for ions, receptors for neurotransmitters, membrane pumps, and the membrane itself. Invertebrate toxins acting on membrane channels include the conotoxins (10) and several of the sea anemone toxins (97). 

Another possible target for toxins are the receptors for neurotransmitters since such receptors are vital, especially for locomotion. In vertebrates the most strategic receptor is that for acetylcholine, the nicotinic receptor. In view of the breadth of action of the various conotoxins it is perhaps not surprising that alpha-conotoxin binds selectively to the nicotinic receptor. It is entirely possible that similar blockers exist for the receptors which are vital to locomotion in lower species. As mentioned previously, lophotoxin effects vertebrate neuromuscular junctions. It appears to act on the end plate region of skeletal muscle (79,59), to block the nicotinic receptor at a site different from the binding sites for other blockers (81). 

HT3 receptor. 5-Hydroxytryptamine receptor a receptor for serotonin (a neurotransmitter), which activates a variety of second messenger signaling systems and through them indirectly regulates the function of ion channels. 

GABA receptors. Receptors for y-aminobutyric acid. GABA is an amino acid that acts as an inhibitory neurotransmitter in the CNS. 

The aim of this chapter is to consider the structure, distribution and functional properties of neurotransmitter receptors in the brain in general and discuss the principles of how the action of drugs at these receptors can be studied. (See relevant Chapters for detail of individual NT receptors.)... 

Today we know not only that there is more than one type of receptor for each neurotransmitter, but we also know a great deal about the structural basis for the differences between receptor subtypes which are due to differences in the amino-acid sequence of the proteins which make up the receptor. How do we know this ... 

Neurotransmitter receptors have evolved as one of the key components in the ability of the central nervous system to coordinate the behaviour of the whole animal, to process and respond to sensory input, and to adapt to change in the environment. These same receptors are therefore ideal targets for drug action because of their central role in the activity of the nervous system. A rational approach to the development of new therapeutic strategies involving the action of drugs at receptors in the nervous system is based on knowledge of receptor structure, distribution and function. 

There is some evidence that receptors for other neurotransmitters on 5-HT nerve terminals also modify release of 5-HT. These include nicotinic receptors (increase release from striatal synaptosomes), a2A-adrenoceptors (depress cortical release) and H3-receptors (cortical depression). Because changes in 5-HT release on activation of these receptors is evident in synaptosomal preparations, it is likely that these are true heteroceptors . 

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