Receptors and ligands

Sarah Teakel

36 Receptors and ligands

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Types of receptors
Signalling molecules

Receptors are protein molecules in the target cell or on its surface that bind ligands. There are two types of receptors, internal receptors and cell-surface receptors.

Types of receptors

Internal receptors

Learning link: Review the structure of the plasma membrane

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell’s DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 7.3). Transcription is the process of copying the information in a cell’s DNA into a special form of RNA called messenger RNA (mRNA); the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Figure 7.3 Hydrophobic signalling molecules typically diffuse across the plasma membrane and interact with intracellular receptors in the cytoplasm. Many intracellular receptors are transcription factors that interact with DNA in the nucleus and regulate gene expression.

Cell-surface receptors

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, through which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain called the extracellular domain, a hydrophobic membrane-spanning region called a transmembrane domain, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor.

Case study

Evolution connection: How viruses recognise a host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to sustain metabolic life. Some viruses are simply composed of an inert protein shell enclosing DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular apparatus. But how does a virus recognise its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for example, humans) often cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in newly produced viruses; these changes mean that the viral proteins that interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with new binding properties comes into contact with a suitable host. In the case of influenza, this situation can occur in settings where animals and people are in close contact, such as poultry and swine farms.¹ Once a virus jumps the former “species barrier” to a new host, it can spread quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the likelihood of global viral epidemics.

Cell-surface receptors are involved in most of the signalling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the double layer of phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the protein’s structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through (Figure 7.4).

Figure 7.4 Gated ion channels located in the plasma membrane allow for the controlled flow of ions into and out of the cell. The channel proteins remain closed until a signalling molecule (orange teardrop) binds to the channel protein. Then the channel protein changes conformation and allows ions (yellow circles) to flow into (or out of) the cell. When the signalling molecule is released, the channel protein resumes its closed conformation, preventing ion flow. Credit: Rao, A. and Fletcher, S. Department of Biology, Texas A&M University. CC BY 4.0.

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane (Figure 7.5). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signalling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a site on the receptor specific for its binding. Once the ligand binds to the receptor, the resulting change in shape activates the G-protein, which releases guanosine diphosphate (GDP) and picks up guanosine 3-phosphate (GTP). The subunits of the G-protein then split into the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active α subunit of the G-protein is hydrolysed to GDP and the βγ subunit is deactivated. The subunits re-associate to form the inactive G-protein and the cycle begins again.

The diagram illustrates the signaling process of a heterotrimeric G-protein in four cyclic stages. Heterotrimeric G-proteins have three subunits: α, β, and γ. When a signalling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with the α subunit is exchanged for GTP. The β and γ subunits dissociate from the α subunit, and a cellular response is triggered either by the α subunit or the dissociated βγ pair. Hydrolysis of GTP to GDP terminates the signal. — Figure 7.5 Heterotrimeric G-proteins have three subunits: α, β, and γ. When a signalling molecule binds to a G-protein-coupled receptor in the plasma membrane, a GDP molecule associated with the α subunit is exchanged for GTP. The β and γ subunits dissociate from the α subunit, and a cellular response is triggered either by the α subunit or the dissociated βγ pair. Hydrolysis of GTP to GDP terminates the signal.

Dive deeper

Watch Science with Tal. (2023, March 16). Pathway Of Gq G-Protein-Coupled Receptors Explained [Youtube, 6:52mins]

G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health.

Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera.

For example

In cholera, for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.
Transmitted primarily through contaminated drinking water, cholera is a major cause of death in the developing world and in areas where natural disasters interrupt the availability of clean water. The cholera bacterium, Vibrio cholerae, creates a toxin that modifies G-protein-mediated cell signalling pathways in the intestines.

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor (Figure 7.6).

A kinase is an enzyme that transfers phosphate groups from ATP to another protein.

The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signalling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighbouring receptors then bond together, or dimerise. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.

This illustration shows two receptor tyrosine kinase monomers embedded in the plasma membrane. Upon binding of a signaling molecule to the extracellular domain, the receptors dimerize. Tyrosine residues on the intracellular surface are then phosphorylated, triggering a cellular response. The cellular response involves binding of relay proteins, which result in Cellular Response 1 and Cellular Response 2. — Figure 7.6 A receptor tyrosine kinase is an enzyme-linked receptor with a single helical transmembrane region, and extracellular and intracellular domains. 2) Binding of a signalling molecule to the extracellular domain causes the receptor to dimerise. 3) Tyrosine residues on the intracellular domain are then autophosphorylated, 4) triggering a downstream cellular response. The signal is terminated by a phosphatase that removes the phosphates from the phosphotyrosine residues. Credit: Rao, A., Ryan, K., Tag, A., Fletcher, S. and Hawkins, A. Department of Biology, Texas A&M University. CC BY 4.0

Case study

A 7-year-old female Kelpie named Rosie was brought to the veterinary clinic with a noticeable lump in her mammary gland. The owner reported that the lump had been growing over the past few weeks. Upon physical examination, the veterinarian observed a firm, irregular mass in the caudal mammary gland. Fine needle aspiration and subsequent cytological analysis revealed the presence of malignant cells, indicating a mammary gland tumour. Immunohistochemistry testing confirmed overexpression of HER2, a receptor tyrosine kinase known to be involved in aggressive tumour growth.
Given the HER2-positive status of the tumour, the veterinary oncologist recommended a treatment plan that included surgical removal of the tumour followed by targeted therapy. Bella underwent a successful mastectomy to remove the affected mammary gland. Post-surgery, she was treated with Lapatinib, a drug that inhibits HER2 receptor tyrosine kinase autophosphorylation. This treatment aimed to reduce tumour growth by disrupting the signaling pathways responsible for uncontrolled cell division. Over the following months, Bella showed significant improvement, with a 50 percent reduction in tumour growth and no signs of metastasis (spread).

A chocolate coloured kelpie — Enjie-Kelpie by Spinefly, CC BY-SA 4.0

Reflective question

Besides autophosphorylation, which of the following steps would be inhibited by Lapatinib?

Signalling molecule binding, dimerisation, and the downstream cellular response
Dimerisation, and the downstream cellular response
The downstream cellular response
Phosphatase activity, dimerisation, and the downsteam cellular response

Signalling molecules

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as chemical signals that travel to the target cells to coordinate responses. The types of molecules that serve as ligands are incredibly varied and range from small proteins to small ions like calcium (Ca2+).

Small hydrophobic ligands

Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four fused rings; different steroids have different functional groups attached to the carbon skeleton. Steroid hormones include the female sex hormone, estradiol, which is a type of estrogen; the male sex hormone, testosterone; and cholesterol, which is an important structural component of biological membranes and a precursor of steroid hormones (Figure 7.7). Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.

The molecular structures of estradiol, testosterone, and cholesterol are shown. All three molecules share a four-ring structure but differ in the types of functional groups attached to it. — Figure 7.7 Steroid hormones have similar chemical structures to their precursor, cholesterol. Because these molecules are small and hydrophobic, they can diffuse directly across the plasma membrane into the cell, where they interact with internal receptors.

Water-soluble ligands

Water-soluble ligands are polar and, therefore, cannot pass through the plasma membrane unaided; sometimes, they are too large to pass through the membrane at all. Instead, most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of ligands is quite diverse and includes small molecules, peptides, and proteins.

Other ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation of the tissue. NO has a very short half-life and, therefore, only functions over short distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand), thus restoring blood flow to the heart.