•

•

The coenzyme ATP and the cellular metabolite glutamate are neurotransmitters when they are secreted at synapses.

The gut hormones gastrin, cholecystokinin, and secretin are also present in the central nervous system (CNS), where they have diverse functions as neuromodulators (influencing the release of other neurotransmitters).

•

•

•

•

•

Somatostatin, identified originally as a hypothalamic agent suppressing the secretion of growth hormone from the pituitary, also operates in the CNS as a neurotransmitter or neuromodulator. More than this, it is a paracrine agent in the pancreas and a hormone for the liver.

The transforming growth factor TGFβalso acts as a chemoattractant and as a growth inhibitor.

Insulin acts not only to regulate glucose metabolism, but also as a growth factor and a regulator of food intake.

Noradrenaline (norepinephrine), depending on whether it is released at a synapse or from the adrenal medulla, can be considered as a neurotransmitter or as a hormone.

Thrombin is a growth factor but is also involved in blood clotting as an activator of platelet function.

Hormones

Hormones are commonly released in small amounts at sites remote from the organs they target. On entering the circulation, they are diluted enormously and are subject to enzymes that break them down. Many of them circulate as complexes with specific binding proteins, reducing their free concentration still further. The result of all this is that their level in the vicinity of a target cell is likely to be extremely low and accordingly, the cell receptors must possess high affinity. Another consequence is that although a target cell may react in milliseconds to hormone binding, overall response times are in the range of seconds to hours.

Examples of water-soluble hormones are included in the list of first messengers shown in Table 2.1. Adrenaline and noradrenaline (epinephrine and norepinephrine) are released from the adrenal gland and can act within seconds. The peptide hormones vary considerably in size, ranging from a few amino acids to full-scale proteins. For example, the hypothalamic factor TRH (TSHreleasing hormone) that induces the release of thyroid stimulating hormone (TSH), consists of only 3 amino acid residues, whereas FSH (follicle stimulating hormone) and TSH are heterodimeric glycoproteins each of about 200 residues.

Growth factors

The first reports that fragments of biological tissue could be maintained in a living state in vitro appeared nearly 100 years ago,1 but routine culturing of dispersed cells did not become established until the 1950s. The successful maintenance of dividing mammalian cells depends on the composition of the culture medium. This is traditionally a concoction of nutrients and vitamins in a buffered salt solution. A key ingredient is an animal serum, such as fetal bovine serum. Without such a supplement, most cultured cells will not replicate their DNA and therefore will not proliferate. An important early discovery was that the best mitogenic stimulus (i.e. inducing mitosis or cell division) is provided by natural clot serum and not plasma. A 30 kDa polypeptide released by platelets was later isolated and shown to have mitogenic properties. It was named platelet-derived growth factor, PDGF (see page 303).

PDGF is a member of a class of messengers, the growth factors, comprising over 40 polypeptides, ranging in size from insulin (5.7 kDa) and EGF (6 kDa) to transferrin (78 kDa). As with the hormones, cells have specific high-affinity receptors for growth factors, though binding may elicit multiple effects. Apart from stimulating (or inhibiting) growth, they may also initiate programmed cell death (apoptosis), differentiation, and gene expression. The effects of growth factors, unlike those for hormones, may last for days. Also, unlike the hormones their effects are short range, generally influencing the growth and function of neighbouring cells.

Endocrine (Greek

ενδoν within, κρiνεi to separate) denotes the ‘action at a distance’ of hormones secreted from the ductless glands that may pervade the whole organism, searching out specific target tissues.

Paracrine denotes the action of an extracellular messenger that takes effect only locally.

When a substance affects the same cell from which it has been released, the activity (perhaps part

of a negative feedback pathway) is termed autocrine.

When a cell affects another cell with which it is in contact, usually through membranebound proteins, the mode of communication is termed juxtacrine.

reddening, and the sensation of pain. The drug aspirin possesses antiinflammatory and pain-relieving properties because it inhibits a key enzyme in the pathway generating prostaglandins, such as the vasoconstrictor prostaglandin E2 (Figure 2.1).

Neurotransmitters and neuropeptides

Neurotransmitters are also first messengers, but their release and detection at chemical synapses contrasts strongly with that of endocrine signals. In the presynaptic cell, neurotransmitter-containing vesicles are organized to

release their contents locally into the tiny volume defined by the synaptic cleft. Individual neurons contain only very small quantities of transmitter and this arrangement ensures that an effective concentration is quickly attained within the cleft following the secretion (by exocytosis) of the contents of relatively few vesicles. The released transmitter then diffuses across the cleft and binds to receptors on the postsynaptic cell. On the macroscopic scale, diffusion is a slow process, but across the short distance that separates the preand postsynaptic neurons ( 0.1 m or less), it is fast enough to allow rapid communication between nerves or between nerve and muscle at a neuromuscular junction. Table 2.2 shows the structures of some important neurotransmitters. In the central nervous system glutamate is the major excitatory transmitter, whereas GABA and glycine are inhibitory. Acetylcholine has its most prominent role at the neuromuscular junction, where it is excitatory. Whether an excitatory or inhibitory effect is evoked depends on the nature of the ion channel that is regulated by the neurotransmitter receptor (see page 54).

First messengers with intracellular receptors

There is a class of hormones that differs in several major respects from the first messengers that we have examined so far. These are the steroid and thyroid hormones (see Figure 10.1, page 275). Firstly, since many are hydrophobic they are able to cross the plasma membrane of cells and then interact with receptors that are intracellular. The hormone-bound receptors then bind to DNA and regulate the expression of particular proteins or sets of proteins. For example, the steroid cortisol can penetrate cells and bind to internal glucocorticoid receptors. These, in turn, bring about transcription of DNA sequences and thus the expression of enzymes that lead to glycogen synthesis. Such a process is slow, requiring hours to take effect. It forms a paradigm for the action of steroid and other hormones that bind to nuclear receptors (thyroid hormone, retinoic acid, vitamin D) and many other non-hormonal lipophilic messengers. This form of signalling is discussed in detail in Chapter 10.

In addition to the transcriptional actions of hydrophobic messengers, there is increasing evidence for non-transcriptional effects, which take place rapidly and involve interactions with cell surface receptors. A recently described

Almost 40 years ago there were already indications that oestrogens can cause a rapid (within 15 s) elevation of cAMP in rat uterus.4 Indeed,

as early as 1941, Hans Selye reported that steroids introduced into the peritoneum of rats induce deep anaesthesia within 15 min.5,6

Steroid derivatives as anaesthetics in surgery have been used since the 1950s (hydroxydione sodium or Viadril, 21- hydroxypregnane-3,20- dione sodium succinate).