Transmitter-receptor interaction

Spencer GE, Lukowiak K, Syed NI (2000) Transmitter-receptor interactions between growth cones of identified Lymnaea neurons determine target cell selection in vitro. J Neurosci 20 8077-8086. 

Noise analysis, in particular the evaluation of experimental spectra, has been extensively used for interpreting the kinetics of transport processes in membranes. (See, for example Frehland (1982) and Section 5.5 of this book.) In Chapter 7 an example will be given of how to use stochastic kinetics to obtain stoichiometric and kinetic information referring to the transmitter-receptor interaction at the surface of the postsynaptic membrane of nerve and muscle cells. 

The possibility of the measurement of postsynaptic membrane noise (Katz Miledi, 1972 De Felice, 1981) gives a deeper insight into the details of the chemical mechanism of transmitter-receptor interaction. 

The measurable fluctuations are in the electrical potential or current of postsynaptic cells, and are induced by fluctuations of quantities of chemical components, particularly transmitter, receptor and intermediate molecules. Consequently, it is possible to give a relation between the quantities describing the electrical fluctuations in a postsynaptic cell and the stoichiometric and kinetic parameters of transmitter-receptor interaction. 

Transmitter-receptor interaction can be described by the following simple model scheme ... 

This model for describing transmitter-receptor interaction can be identified with the stochastic model of closed compartment systems. Adopting the fluctuation-dissipation theorem the conductance spectrum of the postsynap-tic cell is determined by three qualitatively different factors ... 

The skeleton model of the slow oscillation in free acetylcholine can be formulated in terms of mass-action kinetics (Csaszar et al., 1983). In principle, instead of setting up a lumped, skeleton model, a more complex model could be defined to take into account the details of subprocesses (synthesis, storage and release of ACh, cleft processes, transmitter-receptor interaction, diffusion, re-uptake). Experimental information, however, certainly would not be sufficient to parametrise such kinds of models. 

Erdi, P. Ropolyi, L. (1979). Investigation of transmitter-receptor interactions by analyzing postsynaptic membrane noise using stochastic kinetics. Biol. Cyb., 32, 41-5. 

Intercellular communication in the nervous system is typically mediated through synaptic transmission via the release of neurotransmitters and their subsequent binding to specific receptors. The transmitter-receptor interaction then elicits changes in ion channel permeability and/or second messenger formation in the innervated cell. Neurotransmitters can also interact with receptors located on the presynaptic terminal (either autoreceptors, which are activated by the same transmitter, or heteroreceptors, which are activated by a different transmitter released by a different neuron) to regulate the presynaptic function, often by influencing neurotransmitter release. Termination of synaptic neurotransmission depends upon the removal of neurotransmitter molecules from the synaptic cleft by either enzymatic degradation or by reuptake into the presynaptic terminal. 

Histaminergic neurons can regulate and be regulated by other neurotransmitter systems. A number of other transmitter systems can interact with histaminergic neurons (Table 14-1). As mentioned, the H3 receptor is thought to function as an inhibitory heteroreceptor. Thus, activation of brain H3 receptors decreases the release of acetylcholine, dopamine, norepinephrine, serotonin and certain peptides. However, histamine may also increase the activity of some of these systems through H, and/or H2 receptors. Activation of NMDA, p opioid, dopamine D2 and some serotonin receptors can increase the release of neuronal histamine, whereas other transmitter receptors seem to decrease release. Different patterns of interactions may also be found in discrete brain regions. 

A completely different type of effect is observed in metabotropic receptors (bottom right). After binding of the transmitter, these interact on the inside of the postsynaptic membrane with Gproteins (see p. 384), which in turn activate or inhibit the synthesis of second messengers. Finally, second messengers activate or inhibit protein kinases, which phosphorylate cellular proteins and thereby alter the behavior of the postsynaptic cells (signal transduction see p.386). 

The interactions between transmitters and their receptors are readily reversible, and the number of transmitter-receptor complexes formed is a direct function of the amount of transmitter in the biophase. The length of time that intact molecules of acetylcholine remain in the biophase is short because acetylcholinesterase, an enzyme that rapidly hydrolyzes acetylcholine, is highly concentrated on the outer surfaces of both the prejunctional (neuronal) and postjunctional (effector cell) membranes. A rapid hydrolysis of acetylcholine by the enzyme results in a lowering of the concentration of free transmitter and a rapid dissociation of the transmitter from its receptors little or no acetylcholine escapes into the circulation. Any acetylcholine that does reach the circulation is immediately inactivated by plasma esterases. 

Opioids basically exert their analgesic effects by inhibiting synaptic transmission in key pain pathways in the spinal cord and brain. This inhibitory effect is mediated by opioid receptors that are located on both presynaptic and postsynaptic membranes of pain-mediating synapses (Fig. 14—2). In the spinal cord, for example, receptors are located on the presynaptic terminals of primary (first-order) nociceptive afferents, and when bound by opioids, they directly decrease the release of pain-mediating transmitters such as substance P.35,38 Opioid drug-receptor interactions also take place on the postsynaptic membrane of the secondary afferent neuron—that is, the second-order nociceptive afferent neuron in the spinal cord.19,33 When stimulated, these receptors also inhibit pain transmission by hyperpolarizing the postsynaptic neuron.19... 

On the postsynaptic side, there are specific receptors located in the membrane on to which the transmitter binds, in a similar way to the type of hormone-receptor interaction proposed in the previous chapter. (It is also possible that cAMP is involved in the postsynaptic response to some transmitters.) The transmitter-receptor results in a change in the postsynaptic membrane structure. If the receptor is an excitatory one, this may result in an influx of Ca++ ions large enough for the postsynaptic membrane to become depolarized. If a sufficient number of synapses transmit excitatory messages to the postsynaptic nerve at around the same time, the result will be a general depolarization, and the second nerve wil 14 fire or the muscle contract. 

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