Pharmacological Sciences

The nervous system and synaptic signalling by neurotransmitters

The nervous system has two divisions:

• The central nervous system (CNS) consists of the brain and spinal cord.

• The peripheral nervous system consists of cranial and spinal nerves. It includes the autonomic nervous system.

The peripheral nervous system relays information to and from the central nervous system. The brain is the centre of activity that integrates this information and initiates responses.

The autonomic nervous system (part of the peripheral nervous system) has two divisions: sympathetic and parasympathetic. Often, they function in opposition to one

Figure 7 Divisions of the autonomic nervous system. Reprinted from Seeley et al., Anatomy and Physiology, 5th edn., © (2000), McGraw-Hill, with permission from the McGraw-Hill Companies.

another; i.e. when an organ receives both sympathetic and parasympathetic impulses, the responses are opposites (Figure 7):

• The neurotransmitter noradrenaline (norepinephrine) is the main actor of the sympathetic system. This system is dominant in stress situations, which include anger and anxiety, as well as exercise. Such stress situations often involve the need for intense physical activity; i.e. the 'fight or flight response'. The involved physiological changes are listed in Table 3.

• The neurotransmitter acetylcholine is the main actor of the parasympathetic system (Table 3). This system dominates in relaxed (non-stress) situations to

Table 3 Autonomic control of body function.

Sympathetic

Organ: Response

Sympathetic

Parasympathetic CH3-C-0-CH2-CH2-N*-(Otyj

Heart (cardiac muscle) Bronchioles (smooth muscle) Iris (smooth muscle) Salivary glands Stomach and intestines

(smooth muscle) Stomach and intestines

(glands) Internal anal sphincter

Urinary bladder (smooth muscle) Internal urethral sphincter

Liver

Sweat glands

Blood vessels in skin and viscera (smooth muscle) Blood vessels in skeletal muscle Adrenal glands

Increase rate Dilate

Pupil dilates Decrease secretion Decrease peristalsis

Decrease secretion

Contracts to prevent defecation Relaxes to prevent urination

Contracts to prevent urination Changes glycogen to glucose Increase secretion Constrict

Dilate

Increase secretion of adrenaline

Decrease rate (to normal) Constrict (to normal) Pupil constricts (to normal) Increase secretion (to normal) Increase peristalsis for normal digestion Increase secretion for normal digestion Relaxes for defecation

Contracts for normal urination

Relaxes to permit urination

None None None

None

None

postsynaptic membrane Figure 8 Anatomy of synapse/neuroeffector junction.

promote normal functioning of several organ systems. Digestion will be efficient and the heart will beat at a normal resting rate.

Neurons that transmit impulses to other cells do not actually touch them (Figure 8). To pass on information, neurotransmitters need to be secreted by axonal terminals of neurons. The small gap or space between the axon of one neuron and:

• The dendrites or cell body of the next neuron is called the synapse (or synaptic cleft).

• Muscle or gland cells is called the neuroeffector junction.

The receptors for neurotransmitters are present on the membrane from the innervated cells and may also be present on the nerve endings themselves (where, as 'autoreceptors', they are implicated in the autoregulation of neurotransmitter release).

The target cells for neurotransmitters are no more than 50 nm away from the nerve terminal (i.e. the width of a typical synaptic cleft). Diffusion of neurotransmitters over such small distances takes only a short period of time, so that this type of messenger is capable to induce cellular responses almost instantaneously (e.g. skeletal muscle cells may contract and relax again within milliseconds in response to the neurotransmitter acetylcholine). In contrast, the hormones may be required to travel over quite some distance before reaching their target cells, and this delays the onset of the responses. Another difference between neurotransmitters and hormones is that the concentration of the neurotransmitters may become fairly high in the synaptic cleft (>10 M, due to the small volume of the synaptic cleft and the resulting limited dilution). Therefore, there is no need for neurotransmitters to be active at low concentrations.

Small molecule neurotransmitters

A first series of neurotransmitters consist of small molecules (Table 4). They consist of acetylcholine, amino acid derivatives (biogenic amines), amino acids themselves and even molecules (ATP, adenosine) that were initially thought to be strictly cytoplasmic constituents. As an example, dopamine is synthesized within the dopaminergic neuron (Figure 9). This synthesis starts with the amino acid tyrosine (obtained from the diet or from liver phenylalanine), which is converted to L-dopa by tyrosine hydroxylase (TH) in the presence of tetrahydrobiopterin as a cofactor. In other neurones and in chomaffin cells of the adrenal medulla, dopamine can further be transformed into noradrenaline/ norepinephrine (neurotransmitter + hormone) and adrenaline/epinephrine (hormone). Dopamine, noradrenaline and adrenaline contain a catechol (o-dihydroxyphenyl) group and are therefore denoted as 'catecholamines' (Figure 9). Tyrosine hydroxylase is the rate-limiting enzyme in all catecholamine-secreting cells in the body. Those cells which are stained immunocytochemically for tyrosine hydroxylase are thus identified as those producing either dopamine or the other catecholamines noradrenaline and adrenaline.

Table 4 Small neurotransmitter molecules.

Neurotransmitters (small)

Derived from

Site of synthesis

Acetylcholine O

Choline

CNS, parasympathetic nerves

Serotonin = 5-Hydroxytryptamine (5-HT)

GABA

Glutamate

Glutamate

Aspartate Glycine

Histamine hc=c- ch2 - ch2 -nhJ

Adrenaline (epinephrine)

Noradrenaline (norepinephrine)

Noradrenaline (norepinephrine)

Dopamine

Dopamine

Adenosine ATP

Tryptophan CNS, chromaffin cells of the gut, enteric cells

Glutamate CNS

Spinal cord

Histidine Hypothalamus

Tyrosine Adrenal medulla, some CNS cells

Tyrosine CNS, sympathetic nerves

Tyrosine CNS

CNS, peripheral nerves Sympathetic, sensory and enteric nerves

Figure 9 A: Catecholamine biosynthesis. B: Fate of dopamine (DA) in dopaminergic nerve. Reprinted from R.A. Rhoades and G.A. Tanner, Medical Physiology, 1st edn., © (1995), with permission from Lipincott Williams & Wilkins.

Neuropeptides

Many other neurotransmitters are derived from precursor proteins, the so-called peptide neurotransmitters. As many as 50 different peptides have been shown to exert their effects on neural cell function. Among them, p-endorphins are endogenous opiates (which also comprise the enkephalins and the dynorphins, Table 5). P-Endorphins have the same effects as opiate drugs such as morphine.

They can play a role in analgesia in response to stress and exercise. Other functions have been proposed for the P-endorphins, including regulation of body temperature, food intake and water balance. P-Endorphins and other endorphins arise from P-lipotropin, which itself is cleaved from an even larger precursor peptide, proopoiomelanocortin (POMC) (Figure 10). The primary protein product of the POMC gene is a 285 amino acid precursor that can undergo differential processing to yield at least eight signalling peptides (including adrenocorticotropic hormone 'ACTH' and a-melanocyte stimulating hormone 'a-MSH') dependent upon the location of synthesis and the stimulus leading to their production.

In general, neuropeptides are generated from precursor molecules produced in the rough endoplasmic reticulum (RER) and packaged in secretory vesicles or granules in the Golgi stacks. The granules are transported out from the cell body to the terminals (axonal transport) where they release their contents by exocytosis upon stimulation (Figure 11). In contrast, biogenic amines are produced in the cytosol of the cell body, axon and terminal and packaged by uptake in pre-formed granules or vesicles. As a

Table 5 Endogenous opiates and their structures.

Precursor	Endogenous opiate	Structure
Proopiomelanocortin	P-Endorphin	Tyr-Gly-Gly-Phe-Met-Thr-Ser-Gln-Thr-
(POMC)		Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-
		Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-
		Gly-Glu
Proenkephalin A	[Leu5] Enkephalin	Tyr-Gly-Gly-Phe-Leu
	[Met5]Enkephalin	Tyr-Gly-Gly-Phe-Met
	[Met5]Enkephalin-	Tyr-Gly-Gly-Phe-Met-Arg-Phe
	Arg6-Phe7
Prodynorphin	Dynorphin A (1-17)	Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-
(proenkephalin B)		Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gly
	Dynorphin A (1-13)	Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-
		Pro-Lys-Leu-Lys
	Dynorphin A (1-8)	Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile

Figure 10 Peptide messengers derived from the POMC precursor protein.

ACTH 7-lipotropin '/-endorphin p-endorphin

Figure 10 Peptide messengers derived from the POMC precursor protein.

Figure 11 Biosynthesis of neuropeptides in neurons.

Exocytosis insmitter

Transport veside

Figure 11 Biosynthesis of neuropeptides in neurons.

result, amines and peptides may co-exist in granules in varying proportions although their proportions in molecular terms may vary depending on the circumstances.

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