membrane receptors

membrane receptors are specialized protein molecules in the membranes of cells, to which external molecules (hormones, neurotransmitters, drugs) attach, triggering changes in the function of the cell. This process is called transduction: the external signal is transduced into action. Hundreds of receptors are known and there are undoubtedly many more yet to be discovered. Many drugs exert their therapeutic effects by activating or blocking membrane receptors.

Membrane receptors were postulated to exist long before there was any direct evidence for them. The first evidence came from work by the English physiologist Langley on nerve synapses, as long ago as 1889. He painted a solution of the drug nicotine on to ganglia (nodules on sympathetic nerves, containing synaptic connections between axons from the central nervous system and nerve cells whose postganglionic fibres run out to innervate organs such as the heart, eye, and gut). Langley noted that the nicotine caused excitation, then inhibition, of the organs innervated by the postganglionic nerves, implying that it had activated and then blocked the nerve–nerve junctions in the ganglion. Similarly, when nicotine was put on to the junction between motor nerve endings and skeletal muscle fibres, the muscle fibres twitched, suggesting that it mimicked chemical signals released by motor nerves.

When the vagus nerve is stimulated, the heart slows, and Dixon suggested in 1907 that something was set free from the nerve endings to combine with a ‘body’ in the cardiac muscle. The demonstration of chemical transmission had to await the Nobel prize-winning discovery of the German pharmacologist Otto Loewi, reported in 1921. Following an idea for an experiment that he had in a dream, Otto Loewi set up 2 perfused frog hearts such that the perfusate from the first flowed over the second. When the vagus nerve attached to the first heart was stimulated that rate of beating slowed; after a few seconds so did that of the second heart. Some substance (which Loewi called ‘Vagusstoff’), liberated from the first heart, flowed to the second and caused the equivalent of nerve stimulation. Thus the idea was born that there exist receptive sites to receive chemical signals (although this experiment did not prove that the effector substance came from the vagus nerve itself).

Identification of binding sites

Not until the 1950s were attempts made to look for specific binding molecules in cell membranes. Waser used radioactively-labelled curare — which is known to block the receptors for acetylcholine, the neurotransmitter released by motor nerves in skeletal muscle — and showed, by autoradiography (photographic detection of radioactivity), that the material was bound to the muscle at the neuromuscular junction, exactly where the nerve fibres contacted the muscle.

In another seminal study, the British pharmacologists William Paton and Humphrey Rang used radioactive atropine to bind to smooth muscle membranes, where atropine was known to prevent the action of acetylcholine at parasympathetic nerve endings. They detected specific binding molecules of finite size and were thus able to quantify, for the first time, the number of acetylcholine receptors (known here as the muscarinic type) present in smooth muscle.

The naturally-occurring ‘messenger’ substances that bind to receptors on cell membranes are not all neurotransmitters released from nerve endings. Some are hormones, secreted by endocrine glands, and circulating in the blood, which leave through capillary walls to gain access to tissue fluids around their target cells. Others are released by cells to act on other neighbouring cells, as ‘local hormones’ or autacoids.

In general, each receptor is the product of one gene. By now, many receptor genes have been cloned and much is known about the molecular structure and mechanism of the receptors.

Agonists and antagonists

Any substance that binds to a receptor is known as a ligand: those ligands that activate receptors are called agonists, while antagonists occupy receptors without activating them and thereby prevent the action of agonists. In normal circumstances, the ligands acting on our receptors are ‘endogenous’, i.e. they are substances produced within the body itself. However, many drugs cause their therapeutic actions on the body by specifically binding to particular receptors. These drugs are generally not themselves identical to the endogenous ligands, rather they are different substances, extracted from plants or other animals, or synthesized, which act as ‘exogenous’ ligands. There are two reasons for not using endogenous substances as therapeutic drugs. Firstly, many agonist drugs are actually much more effective at activating their receptor than the naturally-occurring endogenous ligand. Secondly, in the case of drugs that work by preventing overactivity of bodily systems, what is needed is an antagonist that binds to the receptor, blocking the action of the endogenous ligand.

You may wonder if all drugs that work by stimulating receptors have equivalent endogenous ligands — in other words, whether the drugs are all reinventions of our own internal chemistry. Consider the pain-relieving drug morphine; it is of plant origin and has a formula unlike anything found in the body. Hans Kosterlitz, working in Aberdeen in the 1970s, maintained that for each non-endogenous agonist there is indeed a corresponding endogenous ligand. He went on with his co-worker John Hughes to discover the enkephalins, the body's natural analgesics, which are the endogenous ligands for the opiate receptors on which morphine acts. The same argument now appears to be true for the cannabinoids, found in marijuana, and the benzodiazepines (such as Valium), which relieve anxiety. There are still many drugs that are thought to act on naturally-occurring receptors for which there are no known endogenous ligands: such receptors are known as ‘orphan’ receptors.

The transduction process

There are important generalizations to be made about receptors and how they transduce their effects. The first consideration is specificity. The body needs to be able to turn on and off specific processes as they are needed. If you are frightened and fleeing from an attacker you do not need to salivate or digest your last meal, but you do need to mobilize all the mental and physical energy you can. Yet there are only a few ways in which a cell can switch on or off a process. Receptor activation by a ‘first messenger’ (hormone or neurotransmitter) can in turn activate key enzymes in the cell or change the concentration of intracellular ions (particularly calcium ions), which act as ‘second messengers’ within the cell, triggering specific processes.

The body achieves specificity by having many ‘first messengers’ and many sorts of receptors and by arranging their disposition. For example there are two types of histamine receptor, H1 and H2. H2 receptors are confined to a few sites, including the stomach, where they are involved in acid production, explaining why the antihistamines that block only the H1 receptor (used to treat allergies) do not prevent gastric acid formation. Different types of cells are programmed by their genes to make only some receptor types and to locate them appropriately. In this way the body is able to respond in a very specific way to different situations.

How do receptors transduce? Clearly, if a receptor is to receive an external chemical signal, part of the protein molecule must be outside the cell. This is the recognition site, which binds specifically with the messenger molecule. When antagonists are bound, the recognition site is blocked and nothing further need happen. Normally antagonists have a high affinity, so that they bind tightly to the receptor for a long period of time. When endogenous or exogenous agonists bind to the receptor then something further must happen in order to transduce the effect. There is, in this situation, a ‘conformational change’, which means the three-dimensional structure of the receptor protein is altered to activate the next stage. While agonists have a high specificity for the binding sites, their affinity is low, so they are soon released to allow further activation by another agonist molecule. For example, when you walk, many groups of muscle fibres in the legs, arms, and torso undergo rapid contractions and relaxations: if the chemical messenger at the receptors were to act for long periods this would be impossible. However, when an anaesthetist wants to relax your abdominal muscles for surgery, a long-acting blocker (an antagonist) is used.

The recognition site in each receptor is joined to the rest of the protein molecule by the transmembrane domain — a chain of amino acids that crosses back and forth across the membrane, ending up with an intracellular terminus. The number of membrane crossings is variable, between as few as two and as many as twelve.

Types of receptor

There are three main receptor families:

G-protein coupled receptors account for 80% of receptors. Here, the intracellular domain of the receptor is bound to one of many sorts of G-protein (G-proteins are so-called because of their high affinity for guanine nucleotides). The conformational change brought about by the agonist causes release the G-protein, which in turn initiates complex interactions, notably the formation of ‘second messengers’.

In ligand-gated ion channels, binding of the agonist causes a structural change in the transmembrane domain, creating a ‘channel’ through which particular ions can flow, into or out of the cell. For instance, nicotinic receptors in muscle form channels that allow sodium ions to enter the muscle when activated by the neurotransmitter acetylcholine, released by motor nerves (or by nicotine). Similarly, so-called GABA receptors on neurons in the brain act as chloride ion channels when stimulated by the inhibitory neurotransmitter GABA.

Tyrosine kinase-linked receptors ‘dimerise’ (forming pairs) when activated by a ligand. In this state they can stimulate tyrosine kinase enzymes in the cell, leading to further effects. The hormone insulin acts on cells in this way.

Alan W. Cuthbert

See also cell signalling; hormones; neurotransmitters.