CHEMICAL MEDIATORS & ANS GENERAL PRINCIPLES OF CHEMICAL TRANSMISSION

Introduction The essential processes in chemical transmission-the release of mediators, and their interaction with receptors on target cells-have been discussed under topics of “How Drugs Act: The Cellular Aspects & Molecular Aspects”, respectively. In this subtopic we consider some general characteristics of chemical transmission of particular relevance to pharmacology.

Dale’s Principle ▾ Dale's principle, advanced in 1934, states, in its modern form: “A mature neuron releases the same transmitter (or transmitters) at all of its synapses.” Dale considered it unlikely that a single neuron could store and release different transmitters at different nerve terminals, and his view was supported by physiological and neurochemical evidence.

Dale’s Principle… It is now known, however, that there are situations where different transmitters are released from different terminals of the same neuron.

Dale’s Principle… Further, most neurons release more than one transmitter (see Co-transmission, below) and may change their transmitter repertoire, for example during development or in response to injury.

The main processes involved in synthesis, storage and release of amine and amino acid transmitters Uptake of precursors; synthesis of transmitter; uptake/transport of transmitter into vesicles; degradation of surplus transmitter; depolarisation by propagated action potential; influx of Ca2+ in response to depolarisation; release of transmitter by exocytosis;

The main processes involved in synthesis, storage and release of amine and amino acid transmitters diffusion to postsynaptic membrane; interaction with postsynaptic receptors; inactivation of transmitter; reuptake of transmitter or degradation products by nerve terminals; uptake of transmitter by non-neuronal cells; interaction with presynaptic receptors.

BASIC STEPS IN NEUROCHEMICAL TRANSMISSION: SITES OF DRUG ACTION The main processes involved in synthesis, storage and release of amine and amino acid transmitters. 1, Uptake of precursors; 2, synthesis of transmitter; 3, uptake/transport of transmitter into vesicles; 4, degradation of surplus transmitter; 5, depolarisation by propagated action potential; 6, influx of Ca2+ in response to depolarisation; 7, release of transmitter by exocytosis; 8, diffusion to postsynaptic membrane; 9, interaction with postsynaptic receptors; 10, inactivation of transmitter; 11, reuptake of transmitter or degradation products by nerve terminals; 12, uptake of transmitter by non-neuronal cells; and 13, interaction with presynaptic receptors. The transporters (11 and 12) can release transmitter under certain conditions by working in reverse. These processes are well characterised for many transmitters (e.g. acetylcholine, monoamines, amino acids, ATP). Peptide mediators (see Ch. 19) differ in that they may be synthesised and packaged in the cell body rather than the terminals.

Denervation Supersensitivity It is known, mainly from the work of Cannon on the sympathetic system, that if a nerve is cut and its terminals allowed to degenerate, the structure supplied by it becomes supersensitive to the transmitter substance released by the terminals. Thus skeletal muscle, which normally responds to injected acetylcholine only if a large dose is given directly into the arterial blood supply, will, after denervation, respond by contracture to much smaller amounts.

Denervation Supersensitivity… Other organs, such as salivary glands and blood vessels, show similar supersensitivity to acetylcholine and noradrenaline when the postganglionic nerves degenerate, and there is evidence that pathways in the central nervous system show the same phenomenon.

Denervation Supersensitivity… Several mechanisms contribute to denervation supersensitivity, and the extent and mechanism of the phenomenon varies from organ to organ. Reported mechanisms include the following: - Proliferation of receptors - Loss of mechanisms for transmitter removal. - Increased postjunctional responsiveness

Denervation Supersensitivity… Supersensitivity can occur, but is less marked, when transmission is interrupted by processes other than nerve section. Pharmacological block of ganglionic transmission, for example, if sustained for a few days, causes some degree of supersensitivity of the target organs, and long-term blockade of postsynaptic receptors also causes receptors to proliferate, leaving the cell supersensitive when the blocking agent is removed.

Denervation Supersensitivity… Phenomena such as this are of importance in the central nervous system, where such supersensitivity can cause 'rebound' effects when drugs that impair synaptic transmission are given for some time and then discontinued

Presynaptic Modulation The presynaptic terminals that synthesise and release transmitter in response to electrical activity in the nerve fibre are often themselves sensitive to transmitter substances and to other substances that may be produced locally in tissues (Such presynaptic effects most commonly act to inhibit transmitter release, but may enhance it

Presynaptic Modulation (2) Example is inhibitory effect of adrenaline on the release of acetylcholine (evoked by electrical stimulation) from the postganglionic parasympathetic nerve terminals of the intestine. The release of noradrenaline from nearby sympathetic nerve terminals can also inhibit release of acetylcholine.

Presynaptic Modulation (3) A similar situation of mutual presynaptic inhibition exists in the heart, where noradrenaline inhibits acetylcholine release, as in the myenteric plexus, and acetylcholine also inhibits noradrenaline release. These are examples of heterotropic interactions, where one neurotransmitter affects the release of another.

Presynaptic Modulation (4) Homotropic interactions also occur, where the transmitter, by binding to presynaptic autoreceptors, affects the nerve terminals from which it is being released This type of autoinhibitory feedback acts powerfully at noradrenergic nerve terminals

Presynaptic Modulation (5) Cholinergic and noradrenergic nerve terminals respond not only to acetylcholine and noradrenaline, as described above, but also to other substances; ATP and neuropeptide Y (NPY), nitric oxide, prostaglandins, adenosine, dopamine, 5-hydroxytryptamine, GABA, opioid peptides, endocannabinoids and many other substances

Presynaptic Modulation (6) Presynaptic receptors regulate transmitter release mainly by affecting Ca2+ entry into the nerve. Most presynaptic receptors are of the G-protein-coupled type, which control the function of calcium channels and potassium channels Transmitter release is inhibited when calcium channel opening is inhibited, or when potassium channel opening is increased in many cases, both mechanisms operate simultaneously.

Postsynaptic Modulation Chemical mediators often act on postsynaptic structures, including neurons, smooth muscle cells, cardiac muscle cells, etc., in such a way that their excitability or spontaneous firing pattern is altered. In many cases, as with presynaptic modulation, this is caused by changes in calcium and/or potassium channel function mediated by a second messenger.

Postsynaptic Modulation (2) The slow excitatory effect produced by various mediators, including acetylcholine and peptides such as substance P on many peripheral and central neurons results mainly from a decrease in K+ permeability Conversely, the inhibitory effect of various opioids is mainly due to increased K+ permeability. Benzodiazepine tranquillisers act directly on receptors for GABA to facilitate their inhibitory effect.

Postsynaptic Modulation (3) Drugs such as galantamine act similarly on nAChRs to facilitate the excitatory effect of acetylcholine in the brain, which may have relevance for the use of such drugs to treat dementia. Neuropeptide Y (NPY), which is released as a co-transmitter with noradrenaline at many sympathetic nerve endings and acts on smooth muscle cells to enhance the vasoconstrictor effect of noradrenaline, thus greatly facilitating transmission.

CO-TRANSMISSION It is probably the rule rather than the exception that neurons release more than one transmitter or modulator each of which interacts with specific receptors and produces effects, often both pre- and postsynaptically. The example of noradrenaline/ATP co-transmission at the sympathetic nerve endings

Functional advantage of co-transmission One constituent of the cocktail (e.g. a peptide) may be removed or inactivated more slowly than the other (e.g. a monoamine), therefore reach targets further from the site of release and produce longer-lasting effects.

Functional advantage of co-transmission The balance of the transmitters released may vary under different conditions. At sympathetic nerve terminals, for example, where noradrenaline and NPY are stored in separate vesicles, NPY is preferentially released at high stimulation frequencies, so that differential release of one or other mediator may result from varying impulse patterns

TERMINATION OF TRANSMITTER ACTION Chemically transmitting synapses other than the peptidergic variety invariably incorporate a mechanism for disposing rapidly of the released transmitter, so that its action remains brief and localised. At cholinergic synapses the released acetylcholine is inactivated very rapidly in the synaptic cleft by acetylcholinesterase. In most other cases, transmitter action is terminated by active reuptake into the presynaptic nerve, or into supporting cells such as glia.

Termination of Transmitter Action (2) Different members of the transporter proteins show selectivity for each of the main monoamine transmitters; e.g. the noradrenaline [norepinephrine] transporter, NET, the serotonin transporter, SERT, which transports 5-hydroxytryptamine and the dopamine transporter, DAT). These transporters are important targets for psychoactive drugs, particularly antidepressants, anxiolytic drugs and stimulants. Transporters for glycine and GABA belong to the same family.

Co-transmission and neuromodulation-some examples Co-transmission and neuromodulation-some examples. [A] Presynaptic inhibition. [B] Heterotropic presynaptic inhibition. [C] Postsynaptic synergism. ACh, acetylcholine; ATP, adenosine triphosphate; GnRH, gonadotrophin-releasing hormone (luteinising hormone-releasing hormone); NPY, neuropeptide Y; SP, substance P; VIP, vasoactive intestinal peptide.