Cell signalling: messengers, receptors and the drugs that act on them
A cell passes a message to another by releasing a chemical messenger that a receptor protein in or on the target cell recognises. Messages differ in how far they travel and in the family of chemical that carries them. Whether a messenger can easily cross a membrane bears on whether it can be stored and where it can reach its receptor. A receptor's shape lets it recognise its ligand and respond to it, and receptors fall into four main types. Ligands, many drugs among them, are agonists, partial agonists, antagonists or inverse agonists according to what they do at the receptor.
Communication between cells
The human body is a macro-organism made up of trillions of micro-organisms, its cells. It can function as a single integrated organism because of the ways those cells communicate: as tissues, as organs and through the pathways that connect them.
Messages between cells can be classified into six types by the distance the message travels.
- Intracrine: the messenger is produced within a cell and has its effect within that cell.
- Autocrine: the messenger is released by the cell and acts on receptors on the outer surface of the same cell.
- Juxtacrine: a signal transmitted along a cell membrane affects the emitting cell or the cells it is touching.
- Synaptic: a neurotransmitter is released into a narrow gap between cells and acts on the cell on the opposite side.
- Paracrine: the messenger diffuses over relatively short distances to act on nearby cells. The diffusion may set up a concentration gradient, and cells exposed to a high concentration may respond differently from cells receiving a weaker signal.
- Endocrine: the messenger is released into the bloodstream and acts on target cells in distant tissue. A single hormone can have different effects on different kinds of tissue.
Families of messenger
Many different chemicals can carry a signal from one cell to another, and they fall into four broad categories.
- Hormones are the signalling chemicals of the endocrine system, with distant effects.
- Neurotransmitters are those of the nervous system. They usually work within the synapse between two nerve cells or between a nerve ending and another cell, such as a muscle or a gland.
- Cytokines are the signalling proteins of the immune system and normally have local, paracrine effects.
- Eicosanoids are produced by the oxidation of polyunsaturated fatty acids such as arachidonic acid, and can have autocrine, paracrine or endocrine effects.
The categories are handy for a first sorting of the body's messengers, but their boundaries are sometimes unclear. Hormones can also act locally, in paracrine fashion, on the tissue that produced them. Some neurotransmitters can enter the bloodstream and have endocrine-like effects on distant tissues. Cytokines that enter the bloodstream in large enough amounts can produce a systemic effect, such as a fever.
Chemically, the messengers include lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins and even some gases. Some hormones are proteins, some lipids and some glycoproteins, whereas all cytokines are small proteins.
Crossing the cell membrane
Signalling molecules that cannot easily pass through cell membranes, such as the neurotransmitters, are often made ahead of time and stored in membrane-bound vesicles inside the cell. They are released when a vesicle is brought to the surface and its membrane fuses with the cell membrane, a process called exocytosis. Those that pass easily through membranes, such as the eicosanoids, cannot be stored inside a cell for that reason. Their production is instead tightly regulated.
Because the fat-soluble messengers, the steroid hormones among them, easily pass through cell membranes, they can reach receptors inside the target cell. To travel in the blood, however, they generally have to be bound to a transport protein, and while they are bound they cannot enter the cell to reach a receptor there. Most of the testosterone in the bloodstream, for example, is bound to albumin or to sex-hormone–binding globulin. Only a tiny proportion is free, and only the free molecules can enter the cell to exert an effect. So conditions that alter the amount of sex-hormone–binding globulin in the bloodstream can alter the amount of free testosterone, and therefore the hormone's effect in the body. The water-soluble messengers travel easily in the blood but typically cannot cross the membrane. They act instead by binding the extracellular portion of a receptor protein that passes through the membrane of the target cell.
Receptors and ligands
Signalling chemicals exert their effects by interacting with a protein that serves as a receptor, and a chemical that binds to a receptor is called a ligand.
A ligand binds specifically to a particular receptor, as a key fits a particular lock. A receptor's precise, predictable shape lets it bind some ligands and not others. Binding can in turn change the receptor's shape, and it is this conformational change that triggers the receptor's physiological effect.
Many receptors can be seen as an intermediate point in a signalling pathway. Once activated, they pass along a signal that is eventually carried to some other target in the cell, where the physiological effect is produced.
Receptor names, families and subtypes
Receptors are named after their ligand. They are divided into families, marked by a subscript number, and the families into subtypes, marked by a subscript letter. As of 2017, fourteen serotonin (5-HT) receptors had been discovered, divided into seven families, 5-HT1 to 5-HT7. The 5-HT1 family includes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F.
Different kinds of cells express different subtypes, so a single ligand can have different effects on different kinds of tissue. In the upper respiratory tract, histamine binds one type of histamine receptor, which triggers allergy symptoms. In the lining of the stomach, it binds another type, which triggers the release of stomach acid.
Types of receptor
There are four main types of receptor protein. Types 1 to 3 are transmembrane receptors, which pass through the cell membrane and are anchored in the cell membrane by one or more transmembrane domains, which are hydrophobic alpha helices. Each needs at least one domain outside the cell to interact with the ligand and at least one inside to interact with molecules there.
- Type 1 receptors are ionotropic receptors, or ligand-gated transmembrane ion channels. When the proper ligand binds, the change in the receptor's shape lets small, electrically charged particles such as K+, Na+, Ca++ and Cl– pass through the membrane.
- Type 2 receptors are metabotropic or G-protein-coupled receptors, sometimes called 7-transmembrane domain receptors because they cross the membrane seven times. They do not open a channel directly. They are linked to a G protein inside the cell, and the activated receptor changes the G protein's shape, which then activates another molecule, the secondary messenger. In some cases the secondary messenger opens ion channels elsewhere on the membrane, and in others it activates other intermediate molecules inside the cell. Regulation of the secondary messenger lets the signal be amplified or suppressed within the cell. Hundreds of these receptors have been discovered, among them the adrenergic receptors, targets of the catecholamines, especially norepinephrine and epinephrine.
- Type 3 receptors are kinase-linked and related receptors. They have a single extracellular domain containing the ligand-binding site, a single transmembrane alpha helix and an intracellular domain that often has an enzymatic function. The receptor tyrosine kinases belong to a larger family of protein tyrosine kinases, many of which have no transmembrane domain. The insulin receptor is a type 3 receptor.
- Type 4 receptors are nuclear receptors, although they are generally found in the cytoplasm and migrate to the nucleus after binding their ligand. They can bind DNA directly and regulate the expression of adjacent genes, so they are classified as transcription factors. They have a C-terminal ligand-binding region, a core that recognises a particular DNA sequence, and an N-terminus that can interact with other factors that alter the receptor's activity. Receptors for the steroid and thyroid hormones are examples.
Changes in receptor expression
Receptor expression is typically dynamic. Chronic stimulation of receptors often reduces their response, either through a fall in the number of receptors or through homologous desensitisation, the uncoupling of some receptors from their intracellular signalling cascade. Repeated stimulation can also cause heterologous desensitisation, in which other receptors that work through a similar mechanism become desensitised as well as the stimulated one.
Binding affinity
The bond between a ligand and its receptor usually results from ionic bonds, hydrogen bonds and Van der Waals forces rather than from covalent bonding, so it is reversible. The reversal is called dissociation.
The strength of the forces holding a ligand and its receptor together is the binding affinity. A ligand with high affinity for a receptor will generally achieve a high degree of occupancy, more of the receptors being bound. High affinity does not necessarily mean a longer residence time, the duration of the ligand–receptor complex.
High-affinity binding might be expected to be more likely to produce a physiological effect, since some of the binding energy could be used to create a conformational change. Some ligands, however, can bind tightly without triggering the receptor's normal response. Naloxone is useful as an antidote to opioid overdose because it has extremely high affinity for µ-opioid receptors but does not produce the normal physiological effects of an opioid drug.
Classes of ligand and the drugs among them
Ligands are classified by the effect they exert on their receptor, and many drugs work on receptors, often by mimicking or blocking the natural ligand. Drug designers often try to develop a compound that binds selectively to only some subtypes of a receptor, typically to obtain the desired effects without undesired side effects.
- An agonist triggers a physiological effect by binding to a receptor. A full agonist maximally stimulates the receptor and has high positive intrinsic activity. Some drugs work by mimicking a natural ligand: the dopamine agonists used in Parkinson's disease activate the dopamine receptors in the brain, so their effect is similar to that of natural dopamine, which is in short supply in those patients.
- A partial agonist only partially activates the physiological response and has low positive intrinsic activity. With no full agonist present, it can provide some stimulation. With a full agonist present, it acts as a competitive antagonist and, by competing for occupancy, can produce a net decrease in receptor activation. Many phytoestrogens, plant-derived oestrogens, are partial agonists of oestrogen receptors and end up with a net antioestrogenic effect because they compete with the full agonist for occupancy. Some drugs, such as buspirone, have a mix of full and partial agonist effects on different receptor subtypes.
- An antagonist occupies the receptor but blocks its physiological effect, which is why antagonists are sometimes called blockers. It has zero intrinsic activity, producing no effect if the natural ligand is absent. Antihistamines are histamine receptor antagonists. There are four types of histamine receptor, and antagonists of each have potential clinical uses: those of the first type treat allergic reactions, those of the second suppress the release of stomach acid, those of the third were being investigated for narcolepsy and Alzheimer's disease, and one of the fourth for atopic dermatitis.
- An inverse agonist has the effect opposite to an agonist's. For that, the receptor must have some basal activity even in the absence of its ligand. By blocking the receptor, the inverse agonist can produce a lower level of activity than is seen with no ligand at all, so it has negative intrinsic activity. Its effect can be blocked by an antagonist. Many antipsychotic, antidepressant and other psychiatric medications have been shown to have inverse activity at various types of receptor.
Many drugs work by letting the natural ligand have more effect. The selective serotonin reuptake inhibitors and the serotonin and norepinephrine reuptake inhibitors let their neurotransmitters stay longer in the synapse, giving them more time to interact with their receptors. As a result, these drugs increase serotonergic, and sometimes noradrenergic, signalling.