Categories of Cell Signaling

How does a particular ligand reach a particular cell? There are five categories of chemical signaling found in multicellular organisms: direct, autocine, paracrine, endocrine, and pheromone. Each of these types of signaling are briefly described below.

The video below provides a concise overview of a few of these process above:

Functions and Types of Hormones

The information below was adapted from OpenStax Biology 37.2, and OpenStax Biology 9.2

The rest of this reading focuses on chemical signaling via hormones (endocrine signaling). Though we tend to think of them as associated with animals, hormones function in cell signaling in all multicellular organisms and, arguably, even in single-celled microbes (more on that at the end of this reading).  Hormones are defined by shared function rather than shared structure. A molecule is a hormone if it:

• is secreted from a cell or gland into the vascular system (or environment, in the case of microbes)
• acts on distant cells in other locations in the body (or community, in the case of microbes)
• causes large effects even with only small amounts of the molecule
• causes a response only in specific target cells
• causes a characteristic response (always the same response in a given set of circumstances)
• is part of a feedback loop (either positive or negative)

Hormones regulate many different functions, including homeostasis, development, reproduction, and stress. They cause responses via a number of pathways, including changes in gene expression and/or activity levels of proteins already present in the cell. Hormones are also highly specific: even though hormones circulate throughout the body and come into contact with many different cell types, they only affect cells that possess the necessary receptors. Receptors for a specific hormone may be found on many different cells or may be limited to a small number of specialized cells. Cells can have many receptors for the same hormone but often also possess receptors for different types of hormones. The number of receptors that respond to a hormone determines the cell’s sensitivity to that hormone, and the resulting cellular response. Additionally, the number of receptors that respond to a hormone can change over time, resulting in increased or decreased cell sensitivity.

As noted above, hormones are defined by a common function rather than a common structure, and there are four general structural classes of hormones:

• peptide hormones are small proteins
• amino acid-derived hormones are modified amino acids (the building blocks of proteins)
• steroid hormones are small organic compounds with characteristic carbon ring structures
• gas hormones are gases capable of acting like ligands

Why do these categories matter?  It has to do with how and where the hormone interacts with the cell receptor. Peptide and amino acid-derived hormones tend to be hydrophilic (soluble in water), and thus cannot cross the cell’s hydrophobic plasma membrane. Thus these hormones bind to receptors on the cell’s surface. In contrast, steroid and gas hormones are both able to cross the plasma membrane because they are small and nonpolar; their receptors are located within the cell.

Hormone Signaling Pathways and Steps

The information below was adapted from OpenStax Biology 9.2 and Khan Academy Ligands & receptors. All Khan Academy content is available for free at www.khanacademy.org

Step 1: signal reception. The first step in hormone signaling is the hormone binding to the receptor. This can occur either inside the cell or on the cell surface, depending on the class of hormone.

Nonpolar , hydrophobic ligands (such as steroid and gas hormones) that are able to travel across the plasma membrane bind to internal receptors, also known as intracellular or cytoplasmic receptors, found in the cytoplasm of the cell. Once the hormone binds, the receptor changes shape, allowing the receptor-hormone complex to enter the nucleus (if it wasn’t there already) and cause changes in gene expression. Hormone binding exposes regions of the receptor that have DNA-binding activity, meaning they can attach to specific sequences of DNA. These sequences are found next to certain genes in the DNA of the cell, and when the receptor binds next to these genes, it alters their level of transcription.

Hydrophobic signaling 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. Image credit: OpenStax Biology

Many signaling pathways, involving both intracellular and cell surface receptors, cause changes in the transcription of genes. However, intracellular receptors are unique because they cause these changes directly, binding to the DNA and altering transcription themselves.

In contrast, hydrophilic ligands (such as peptide and amino acid-derived hormones) which cannot cross the cell plasma membrane must bind to cell-surface receptors, also known as transmembrane receptors, on the cell surface. Instead of directly changing the behavior or gene expression in a cell, cell-surface receptors perform signal transduction, or the process of converting an extracellular signal into an intercellular signal. Thus the receptor does not alter gene expression directly, but must activate chemical or protein “messengers” to relay the signal from outside to inside the cell.

The chains of molecules that relay signals inside a cell are known as intracellular signal transduction pathways. Image credit: Khan Academy.

 

Step 2: signal transduction. Signal transduction, or changing an extracellular signal into an intracellular signal, is only necessary for hydrophilic ligands that cannot cross the plasma membrane.

Once a hormone binds to the extracellular portion of the cell-surface receptor, the intracellular portion of the receptor changes shape, resulting in activation of a chain of events that is called a signaling pathway or signaling cascade. The events in the cascade occur in a defined series of events. Many different enzymes are activated by different specific receptors, but in general this activated enzyme then activates other proteins which carry the signal into the cell to elicit a response. Pathways activated by cell surface receptors include synthesis of second messengers (non-protein signaling molecules) such as calcium or cyclic AMP which propagate throughout the cell to spread the signal, or initiation of a phosphorylation cascade where a series of proteins are activated by having a phosphate group added to them, which changes their activity. Ultimately the activation of the pathway results in some type of cellular response, which may include changes in gene expression.

Step 3: signal amplification: one feature of hormones is that a very small amount of the hormone can elicit a very strong physiological response. This phenomenon is mediated through a process called signal amplification, where the signal from the hormone is “amplified” or magnified via one of several mechanisms:

• For hydrophilic hormones that bind to cell-surface receptors, the amplification can occur via second messengers, where thousands of molecules are produced or released in response to the hormone signal
• For nonpolar hormones that bind to intracellular receptors, the amplification can occur during the process of both transcription, where hundreds of copies of mRNA are synthesized from a single gene, and during translation, where hundreds of copies of each protein are synthesized from a single mRNA

The video below provides an overview receptor-ligand binding, signal transduction, and a preview cellular responses (covered in the next section):

Responding to the signal

The information below was adapted from OpenStax Biology 9.3, and Khan Academy Signal relay pathways. All Khan Academy content is available for free at www.khanacademy.org

Step 4: signal response: There are many different types of cellular responses to a hormone, including:

• changes in gene expression
• changes in cell metabolism
• cell growth and division

The overall response to a hormone signal can be to amplify the signal and increase the response (positive feedback), or to decrease the signal and decrease the response (negative feedback). The key is that in positive feedback, the response to the stimulus causes the stimulus to continue in the same direction; while in negative feedback, the response to the stimulus causes the stimulus to change direction. So in a positive feedback loop, if the stimulus is increasing, then the response to the stimulus causes it to increase even more. In a negative feedback loop, if the stimulus is increasing, then the response will cause the stimulus to decrease. Positive and negative feedback loops are important mechanisms of cellular and organismal regulation.

This video (beginning at 1:13) provides an overview of positive vs negative feedback loops (watch through at least 5:58):

The response to a particular signal can be very straightforward, but there can be differences between different cell types and in different conditions for a number of reasons:

• The same ligand can cause different responses in different cell types due to differences in protein expression in the different cells, where the same signal activates different signaling pathways, leading to a different response in each cell type.
• The same ligand can cause different responses in different cell types due to different receptors in the two different cell types, which then activate different signaling pathways, leading to different responses in each cell type.
• Often multiple signaling pathways interact with each other because the same signaling proteins are involved in each pathway. As a result, if two different signals come in at the same time, the outcome can be different than if they came in separately. The phenomenon where the outcome can change based on interactions between different signaling pathways is called signaling crosstalk.

Signaling in single-celled organisms

The information below was adapted from OpenStax Biology 9.0 and OpenStax Biology 9.4, OpenStax Biology 22.1, Khan Academy Cell-cell signaling in unicellular organisms, and Wikipedia Quorum sensing. All Khan Academy content is available for free at www.khanacademy.org

In multicellular organisms, cells send and receive chemical messages constantly to coordinate the actions of distant organs, tissues, and cells. The ability to send messages quickly and efficiently enables cells to coordinate and fine-tune their functions.

While the necessity for cellular communication in larger organisms seems obvious, even single-celled organisms communicate with each other. For example, yeast produce chemical signals that allow them to find mates. Some species of bacteria coordinate their actions in order to form large complexes called biofilms, or to organize the production of toxins to kill competing organisms. The ability of cells to communicate through chemical signals originated in single cells and was essential for the evolution of multicellular organisms.

We will focus on a phenomenon called quorum sensing in bacteria, a phenomenon where individual bacteria monitor the density of their population; once the population reaches a specific density, the bacteria collectively change their gene expression and behavior at the same time. Quorum sensing is used to control a number of behaviors that would be difficult or even detrimental for one or a few bacteria to perform, but which become successful and highly adaptive if performed by a large group at the same time. Because the number of cells present in the environment (cell density) is the determining factor for signaling, bacterial signaling is named quorum sensing; in politics and business, a quorum is the minimum number of members required to be present to vote on an issue. Behaviors regulated by quorum sensing include (but are not limited to):

• formation of biofilms
• attacking competitors
• luminescence (emitting light)
• activation of virulence genes (associated with pathogenicity, or the ability to cause an infection)

How does quorum sensing work?  It’s all based on continuous secretion of a signaling molecule, or a bacterial hormone, called an autoinducer. If a single cell or just a few cells secrete it, there isn’t much of the molecule in environment, and it doesn’t change the bacteria’s behavior. But as the number of individuals in the population increases, there are more and more cells secreting the hormone, and thus the hormone increases in density. Once it reaches a certain density, it causes a cellular response in all cells at the same time, which then collectively change their behavior based on whatever signaling pathway is activated by the hormone.

Autoinducers are small molecules or proteins produced by bacteria that regulate gene expression through quorum sensing. Image credit: “Signaling in single-celled organisms: Figure 2,” by OpenStax College, Biology (CC BY 3.0).

In general, each species of bacteria has its own autoinducer, with a matching receptor that’s highly specific (won’t be activated by the autoinducer of a different bacterium). However, some types of autoinducers can be produced and detected by multiple species of bacteria. Scientists are investigating how these molecules may allow for between-species communication.

We’ll describe a few examples of behaviors controlled by quorum sensing below:

Symbiosis and bioluminescence: Quorum sensing was first discovered in Aliivibrio fischeri, a bacterium that has a symbiotic (mutually beneficial) relationship with the Hawaiian bobtail squid. A. fischeri form colonies inside the squid’s “light organ.” The squid gives the bacteria food, and in return, the bacteria bioluminesce (emit light). The glow of the bacteria prevents the squid from casting a shadow, hiding it from predators swimming beneath.

Image credit: Khan Academy, modified from “Euprymna scolopes,” by Chris Frazee and Margaret McFall-Ngai (CC BY 4.0)

Biofilm formation: Some species of quorum-sensing bacteria form biofilms, surface-attached communities of bacterial cells that stick to one another and to their substrate (underlying surface). Biofilms can be quite complex, with bacterial cells organizing to form ordered structures, and some biofilms contain multiple species of coexisting bacteria.

Biofilms are present almost everywhere: they can cause the clogging of pipes and readily colonize surfaces in industrial settings. They produce dental plaque and colonize catheters, prostheses, transcutaneous and orthopedic devices, contact lenses, and internal devices such as pacemakers. They also form in open wounds and burned tissue. In healthcare environments, biofilms grow on hemodialysis machines, mechanical ventilators, shunts, and other medical equipment. In fact, 65 percent of all infections acquired in the hospital (nosocomial infections) are attributed to biofilms. Biofilms are also related to diseases contracted from food because they colonize the surfaces of vegetable leaves and meat, as well as food-processing equipment that isn’t adequately cleaned. In recent, large-scale outbreaks of bacterial contamination of food, biofilms have played a major role. They also colonize household surfaces, such as kitchen counters, cutting boards, sinks, and toilets, as well as places on the human body, such as the surfaces of our teeth.

Image of a Staphylococcus aureus biofilm on the surface of a catheter. Image modified from “Signaling in single-celled organisms: Figure 3,” by OpenStax College, Biology (CC BY 3.0). Based on original image by Janice Carr, CDC.

Interactions among the organisms that populate a biofilm, together with their protective exopolysaccharidic (EPS) environment, make these communities more robust than free-living, or planktonic, prokaryotes. The sticky substance that holds bacteria together also excludes most antibiotics and disinfectants, making biofilm bacteria hardier than their free-living counterparts. In addition, individual cells within a biofilm actually take on specialized roles, similar to multicellular organisms, with some cells forming channels to help remove toxins (such as antibiotics) from the biofilm. Once an infection by a biofilm is established, it is very difficult to eradicate, because biofilms tend to be resistant to most of the methods used to control microbial growth, including antibiotics and detergents. Biofilms respond poorly or only temporarily to antibiotics; it has been said that they can resist up to 1,000 times the antibiotic concentrations used to kill the same bacteria when they are free-living. An antibiotic dose that large would harm the patient; therefore, scientists are working on new ways to get rid of biofilms.

Five stages of biofilm development are shown. During stage 1, initial attachment, bacteria adhere to a solid surface via weak van der Waals interactions. During stage 2, irreversible attachment, hairlike appendages called pili permanently anchor the bacteria to the surface. During stage 3, maturation I, the biofilm grows through cell division and recruitment of other bacteria. An extracellular matrix composed primarily of polysaccharides holds the biofilm together. During stage 4, maturation II, the biofilm continues to grow and takes on a more complex shape. During stage 5, dispersal, the biofilm matrix is partly broken down, allowing some bacteria to escape and colonize another surface. Micrographs of a Pseudomonas aeruginosa biofilm in each of the stages of development are shown. (credit: D. Davis, Don Monroe, PLoS)

This video provides a quick overview of the relevance of biofilms to human health:

Research on the details of quorum sensing has led to advances in growing bacteria for industrial purposes. Recent discoveries suggest that it may be possible to exploit bacterial signaling pathways to control bacterial growth; this process could replace or supplement antibiotics that are no longer effective in certain situations.