Cells have the ability to sense what is going on around them and can react to stimuli from their external environment. In fact, your cells are exchanging millions of signals in the form of chemical signaling molecules right now. Each time you think, eat, read, see, move - every one of those functions is carried out by cells that are talking to each other through the release and reception of chemical messengers.
In the following, we will review the definition, types, and process of cell signaling. Then we will discuss in-depth the first stage of cell signaling, called signal reception. Specifically, we will go into the different types of ligands and receptors involved in signal reception. We will also discuss a specific example.
Cell signaling definition
Cell signaling is the process by which a cell reacts to signals–typically chemical in nature–from its external environment through protein receptors. Cell signaling can take place between cells (intercellular signaling) and within the cell (intracellular signaling).
There are various types of cell signaling. Cells can release ligands that bind to receptors within the same cell. This process is called autocrine signaling. Cells can also communicate with nearby cells in a process called paracrine signaling. Cells in an organism can also receive signals via hormones from cells in distant parts of the body. This process is called endocrine signaling.
Three stages of cell signaling: reception, transduction, and response
Cell signaling has three basic stages:
Signal reception: The cell detects a signal when a signaling molecule called a ligand binds to a receptor protein on the cell surface.
Signal transduction: The ligand reconfigures the receptor protein. The signal is relayed by each molecule changing the next molecule in the pathway.
Cellular response: The signal initiates a specific cellular process.
This article will focus on the first step of cell signaling, signal reception.
Definition of signal reception, ligands, and receptors in biology
Signal reception occurs when a ligand binds to a receptor protein in or on the surface of the plasma membrane. A ligand is a molecule that delivers signals, while a receptor is a molecule to which a ligand binds. Upon binding of the ligand, receptors initiate a physiological response.
Both ligands and receptors have a high level of specificity: typically, a ligand binds to a specific receptor. For example, growth factor receptors bind growth factors (and different subtypes of receptors can bind different types of growth factors), and dopamine receptors bind dopamine. In addition to chemical signals, some receptors can also detect light, heat, pressure, and other external stimuli.
Types of ligands
Ligands come in varying forms and sizes. Here we will discuss hydrophobic ligands and water-soluble ligands.
Small hydrophobic ligands
Small hydrophobic ligands such as steroid hormones directly diffuse through the interior of the plasma membrane and interact with internal or cytoplasmic receptors. Some steroid hormones can also bind to receptors located on the cellular surface.
Steroids are lipids with four fused rings on their hydrocarbon skeleton, which are connected to various functional groups depending on the kind of steroid. Testosterone (the male sex hormone), estradiol (the female sex hormone), and cholesterol (a crucial structural element of biological membranes and a precursor to steroid hormones) are all examples of steroid hormones.
Water-soluble ligands
Water-soluble ligands are polar so they cannot pass through the plasma membrane on their own. There are also water-soluble ligands that are too large to enter the membrane at all. As such, most water-soluble ligands bind to cell-surface receptors on the plasma membrane where extracellular signals are turned into intracellular signals. This group of ligands includes peptides and proteins.
Types of cell receptors
There are two types of cell receptors: internal and cell-surface receptors. We will also go into the three main categories of cell-surface receptors.
Internal receptors
Internal receptors--also known as cytoplasmic or intracellular receptors--can be found in the cytoplasm. They typically interact with hydrophobic ligand molecules that move across the plasma membrane. Upon entering the cell, these hydrophobic molecules bind to proteins that regulate transcription as part of gene expression.
Gene expression refers to the biological process in which information in the DNA of a cell is transformed into a sequence of amino acids which becomes a protein. Gene expression takes place in two steps: transcription and translation.
Transcription refers to the process by which information in DNA is copied into an mRNA (messenger RNA) molecule
The binding of the ligand to the internal receptor triggers a conformational change in which a DNA-binding site is exposed on the protein. The complex consisting of the ligand and the receptor moves into the nucleus and binds to certain regions of chromosomal DNA, leading to the initiation of transcription.
Internal receptors do not need to pass signals onto other receptors or messengers in order to influence gene expression.
Cell surface receptors
Cell surface receptors span the plasma membrane, meaning each receptor has extracellular (outside the cell), transmembrane (in the interior of the cell membrane), and cytoplasmic or intracellular (in the cytoplasm) domains.
Unlike internal receptors, cell-surface receptors need to convert extracellular signals into intracellular signals in a process called signal transduction. Ligands that bind with cell-surface receptors are not required to enter the cell.
Cell-surface receptors can be classified into three major categories based on the mechanism by which they reconfigure extracellular signals into intracellular ones: G-Protein-coupled receptors, ion channel receptors, and enzyme-linked receptors.
Ion channel receptors
Ion channel-linked protein receptors work by binding a ligand and then opening a channel across the plasma membrane that allows specific ions to pass through (Fig. 1).
This type of cell surface receptor has a wide membrane-spanning region in which a channel can be constructed. Many amino acids in the transmembrane region are hydrophobic, so they are able to interact with the phospholipid fatty acid tails which constitute the core of the plasma membrane.
On the other hand, amino acids lining the inside of the ion channel are hydrophilic, so they can allow water or ions to pass through. When a ligand attaches to the extracellular region of the channel, the proteins undergo shape change to accommodate the entry of ions like sodium, calcium, and hydrogen.
One example of ion channel receptors are those located on neurons. One such ion channel receptor is the ionotropic glutamate receptor, which binds the ligand glutamate. Glutamate is an excitatory neurotransmitter, that elicits activation of the neuron it binds to. When glutamate binds to ionotropic glutamate receptors, the pore opens and sodium is able to flow into the cell, causing the plasma membrane to become depolarized, which, when threshold is reached, triggers an action potential. As the action potential moves across the cell's surface, it can initiate other cellular processes.
Enzyme-linked receptors
Enzyme-linked receptors are found on the surface of the cell membrane. Some have an intracellular domain that interacts with enzymes, while others have an intracellular domain that is, in itself, an enzyme. Most enzyme-linked receptors have large extracellular and intracellular domains, with the region spanning the membrane consisting of a single alpha-helical region of a peptide strand.
When a ligand binds to the extracellular region, a signal is sent through the membrane, which activates the enzyme. The activated enzyme triggers a series of reactions that leads to a cellular response.
Enzyme-linked receptors allow signaling molecules to influence cell function without actually entering the cell since they interact with both extracellular signals and molecules present inside the cell. This is crucial as the majority of signaling molecules are either charged or too large to pass through the plasma membrane.
G Protein coupled receptors
G protein coupled receptors work by binding a ligand and then activating a type of membrane protein known as a G protein, which then interacts with an ion channel or an enzyme in the plasma membrane. G proteins are made up of several subunits:
G protein coupled receptors span the membrane 7 times and contain a guanine nucleotide exchange (GEF) domain.
As such, when G protein coupled receptors bind ligands, the GEF domain catalyzes Gα to bind GTP. Gα-GTP dissociates from the Gβγ, and then some Gα subunits stimulate the activities of subsequent enzymes in the series, while others inhibit them (Fig. 2).
Example of signal reception in biology
An example of an enzyme-linked receptor is the tyrosine kinase receptor (Fig. 3). A protein kinase adds phosphate groups from ATP to a protein molecule. The tyrosine kinase receptor transfers phosphate groups specifically to tyrosine residues.
When the signal molecules bind to the extracellular region of two adjacent tyrosine kinase receptors, the two receptors undergo dimerization. Then, the tyrosine residues on the intracellular domain of the receptors undergo phosphorylation, enabling them to transmit the signal to the next messenger within the cytoplasm.
An example of receptor tyrosine kinase is HER2. HER2 is permanently active in 30% of human breast tumors, which leads to uncontrolled cell division. HER2 receptor tyrosine kinase autophosphorylation is inhibited by lapatinib, a medication used to treat breast cancer, which slows tumor development by 50%.
Dimerization refers to the process by which two identical molecules are attached via a chemical bond
Phosphorylation refers to the addition of a phosphate group to a molecule
Autophosphorylation refers to the the process by which the receptor attaches phosphates onto itself
Signal Reception - Key takeaways
- Cell signaling has three basic steps: signal reception, signal transduction, and cellular response.
- Signal reception is the stage in which the ligand binds to a receptor protein in or on the surface of the plasma membrane.
- There are two types of receptors: internal and cell surface receptors.
- Internal receptors do not need to pass signals onto other receptors or messengers.
- Cell surface receptors reconfigure extracellular signals into intracellular ones through signal transduction.
References
- “Intro to Chemical Signaling and Communication by Microbes.” Organismal Biology, https://organismalbio.biosci.gatech.edu/chemical-and-electrical-signals/intro-to-chemical-signaling-and-signal-transduction/. Accessed 30 June 2022.
- Cell Biology@Yale. medcell.med.yale.edu, http://medcell.med.yale.edu/lectures/cell_communication.php. Accessed 30 June 2022.
- “Cell Signaling | Learn Science at Scitable.” Cell Signaling | Learn Science at Scitable, www.nature.com, https://www.nature.com/scitable/topicpage/cell-signaling-14047077/. Accessed 30 June 2022.
- OpenStaxCollege. “Signaling Molecules and Cellular Receptors – Biology.” Signaling Molecules and Cellular Receptors – Biology, pressbooks-dev.oer.hawaii.edu, http://pressbooks-dev.oer.hawaii.edu/biology/chapter/signaling-molecules-and-cellular-receptors/. Accessed 30 June 2022.
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