Cell Communication - 1 Just as we communicate with other humans (a number of different ways), cells communicate with other cells, to interact with the external environment and to make appropriate responses within the cellular environment. Cellular communication is necessary to coordinate the myriad activities needed for any organism (unicellular or multicellular) to grow, develop and function. Fortunately for students studying biology, most groups of organisms use the same kinds of cell signals, once more affirming the uniformity of life processes. Cells typically use chemical signals for communication, but electromagnetic signals (light) and mechanical signals (pressure or touch) are not uncommon. Plants in particular respond to a host of external environmental signals. Nerve cells of animals are especially sensitive to stimuli (e.g., chemoreceptors, mechanoreceptors, photoreceptors, thermoreceptors, nocireceptors (pain), electroreceptors). However, cell-to-cell communication is most often chemical, and chemical communication is the subject of this section. Before we begin lets look at a few examples of cell signaling to give you an idea of what we mean: Cellular slime molds secrete chemicals that induce adjacent cells to aggregate into a multicellular "slug" when growth conditions are unfavorable. This slug can disassemble, migrate or form a resistant "fruiting body" depending on the conditions. Myxobacteria do a very similar aggregation forming a resistant colony "spore" when their nutrients are diminished. Many protists and other unicellular organisms are similar in dimension. Gender is determined by genetic "mating types". One individual recognizes an appropriate mate by secreting its mating factor (chemical) for which a compatible mate will have a receptor. In a similar fashion, the compatible mate will secrete its mating factor, for which the original cell has a receptor. These signals binding to the respective membrane receptors of the "mate" trigger the fusion of the two cells. Typically, once a zygote is formed, meiosis occurs and the new generation haploid cells are formed, half of each mating type. By the way, receptiveness to sexual reproduction is one of the more common uses of chemical signals. Female insects secrete pheromones that can be detected by males of the species in ppb as much as a mile distant. (Some orchids produce the same chemical signal to trick an unsuspecting male insect into pollinating the orchid.) Female pigs don't ovulate unless the appropriate male boar scent is detected. There are thousands of sexual selection examples involving chemical attractants.
Cell Communication - 2 Communication of Self In our discussion of membrane proteins we mentioned the recognition proteins, important to the immune system. They play a critical role in communicating to cells of our immune system and to our tissues in recognizing and determining identity. Each cell has unique surface identity markers. Many of these are glycolipds or a group of proteins called MHC (major histocompatibility complex) proteins. The markers that form the A B and O blood groups are examples of glycolipid identity markers. Most of the MHC proteins are immunoglobulins. A section of Biology 202 is devoted to discussion of the immune system and how it interacts with recognition markers. Signals and Receptor Proteins We have previously mentioned that membranes have signal transduction or receptor proteins that have attachment sites for chemical messengers, such as hormones. Receptor proteins are specific; each "fits" a specific chemical messenger molecule. The binding of the signal molecule to its protein receptor induces a conformational change in the receptor protein that ultimately leads to a response within the cell. Individual cells have different receptor proteins. This means that cells uniquely respond only to the signal molecules that are appropriate. Types of Cell Signaling There are a number of types of cell signaling mostly dependent on the distance between the signal and the responding cell. We will mention these briefly before turning to the mechanisms of signal receptors and the signal pathways involved in cell communication. Autocrine Signaling Direct Contact Signaling Paracrine Signaling Endocrine Signaling Synaptic Signaling Autocrine Signaling Cells can send intracellular signals that trigger receptors within their own membrane. Such signals often trigger differentiation in developmental processes.
Cell Communication - 3 Direct Contact Signaling Molecules on the surfaces of adjacent cells have direct contact with each other and specific surface molecules on plasma membranes can serve as signals. For example, cell recognition markers are important in embryo develop as they signal adjacent cells to specialize for a specific tissue type and/or inhibit specialization. Paracrine Signaling A signal molecule released by one cell travels through the extracellular environment and acts on the receptor molecule of adjacent cells in paracrine signaling. The influence of the signal molecule is short-lived, as it reacts with the receptor cell and is removed from the environment. Growth regulators are typically paracrine molecules. Endocrine Signaling We are probably most familiar with endocrine signals. Chemicals produced in one cell or tissue travel through the organism to the target cells and tissues. Many of these signal molecules are our regulatory hormones. Details of endocrine functions are discussed in both Biology 202 and 203. Synaptic Signaling The signal molecules of the nervous system of animals are chemical. Neurotransmitters, released at the axon end of one nerve cell traverse the space (called the synaptic cleft) to the target cells (receptor cells, nerve cells, or neuromuscular junction). Neurotransmitter signal molecules and nerve function are discussed in Biology 202.
Cell Communication - 4 Signal Pathways The mechanisms for chemical messaging that occur in yeasts, bacteria, plants and animals are remarkably similar in all groups. Receptor cells on the surface of the plasma membrane induce changes in the cell that elicit appropriate responses, generally some type of chemical reaction or series of metabolic reactions. The series of steps involved is referred to as a signal transduction pathway and there are a variety of methods for signaling. Signaling has been studied most in animals, and the emphasis in this section is on chemical messaging in animal cells. Table 7.1 in your text summarizes the signal receptor mechanisms.
Cell Communication - 5 Early Studies of Cell Signaling Earl Sutherland won a Nobel prize for his research on the chemical signaling. He specifically studied the role of epinephrine in promoting the conversion of glycogen to glucose-1-phosphate during stress responses, the effect of which is to mobilize fuel reserve molecules for cell respiration. He is responsible for first determining the stages of cell signaling. When you look at examples of cell signaling, what all have in common is that at some point a chemical signal attaches to a receptor molecule in a plasma membrane. This information carried by this signal molecule is changed in some way (hence the term "transduced") within the cell initiating a process that results in some kind of cellular response. The three stages of cell signaling are, therefore, reception, transduction and response. The three stages of chemical cell signaling: Reception The target cell must be able to detect that a signal is "arriving". This requires a chemical binding to a receptor molecule (protein), specialized for different functions. Most receptor molecules are found on the cell surface, but there area also intracellular receptors. Transduction - Initiating the Intracellular Signal The receptor molecule binds to the signal molecule in a method that brings about a change in the receptor molecule (often a conformational change). This change effectively translates (or transduces) the signal into a form that the target cell can respond to. This transduction may be a single step or a relay pathway of chemical reactions within the cell. Secondary messengers are important in the signal transduction. Response The cell makes an appropriate response to the signal. For example, the appropriate response to epinephrine (studied by Sutherland) in most target cells it the activation of the enzyme, glycogen phosphorylase, which catalyzes the conversion of glycogen to glucose-1-phosphate. Catalyzing a chemical reaction is just one response that can be made to an appropriate signal. A signal can activate genetic transcription, movement of cytoskeletal components, or other activities. Cell signals ensure that the right kind of activity occurs in the cell at the right time and in the proper cell conditions.
Cell Communication - 6 Let's look now at some specific details and examples of cell receptors and signal pathways. The Receptors A signal molecule binds to a specific receptor site on a membrane or within the cytoplasm or the nucleus of the cell for intracellular receptors. Ligand is a term used to describe any small molecule that binds to a larger molecule. Many signal molecules behave like ligands. The signaling molecule has a shape that fits into a portion of its receptor protein, just as a key fits into a specific lock so a door can be opened. Intracellular Receptors Intracellular receptors function with small signal molecules that can readily pass through the plasma membrane. Intracellular receptors either act as enzymes or gene regulators. Gene Regulator Intracellular Receptors Many of our steroid hormones function as signals for gene regulator receptors. These receptors have specific DNA binding sites that are normally blocked by an inhibitor protein. When activated by the signal molecule, the inhibitor is released so that the receptor can bind to DNA to initiate gene activity. Gene controls of transcription will be discussed in more detail later! Enzyme Intracellular Receptors Some enzymes require signal molecules to become active. Signal molecules function much the same way that co-factors and coenzymes work. Each has a binding site on the enzyme that alters the conformation of the enzyme so that the target substrate can "fit". Similarly, many of our digestive enzymes are produced in inactive forms and must be activated in the target location of the digestive system.
Cell Communication - 7 Cell Surface Receptors The signaling molecule has a shape that fits into a portion of its receptor protein in the plasma membrane. The signal transduction is then initiated in the membrane when the receptor protein reacts with its signal. Sometimes the signal molecule promotes a conformational change in the receptor molecule that activates the receptor to interact with a specific cellular molecule or an aggregation of receptor proteins In some cases, the ligand (signal molecule) causes an aggregation of receptor proteins in the plasma membrane. Researchers have determined a number of different types of cell surface receptors involved in signaling in animals. Receptors include: Gated Ion-Channel Receptors G-protein (Guanine-protein) Linked Receptors Protein-Kinase Receptors Ion-Channel Receptors As discussed previously, ion channels are gated pores in the plasma membrane that open and close in response to signals. The pores are highly specific and allow the flow of just one type of molecule (typically Na +, Ca ++ or K + ). Nerve transmission and muscle contraction rely on gated ion channels which, when open, rapidly cause a change in ion concentration as the ions flow through the pore. This change in the polarity of the cytoplasm triggers a reaction or relay reactions. Ligand binds, channel opens, Ligand dissociates, Ligand released ions flow through channel closes
Cell Communication - 8 G-Protein Linked Receptors There are a number or receptor molecules that must work with a special group of helper proteins in membranes called G-proteins. Receptor proteins that work with G-proteins have a common structure. Each is comprised of 7 alpha-helices (a motif) within the membrane, with an attachment site for the G-protein on the cytoplasmic side and for the signal molecule on the extracellular side of the membrane. How G-Proteins Work G-proteins are intermediates in cell signal pathways. In their non-active form, G- proteins have guanine diphosphate (GDP) attached. The active form of a G-protein has guanine triphosphate (GTP). GTP is formed when ATP is used to phosphorylate GDP. A ligand attaching to the receptor molecule triggers (by inducing a conformational change in) the receptor molecule to activate its associated G-protein by causing GTP to displace the inactive GDP on the G-protein. In general, the activated G-protein then binds to a specific enzyme in the membrane, activating the enzyme which catalyzes a signal pathway in the cell resulting in a specific cell response.
Cell Communication - 9 This activation is short-term. The GTP is rapidly hydrolyzed back to GDP in the cell by the enzymatic activity of the G-protein. (A G-protein serves as its own enzyme to catalyze the reaction of GTP --> GDP.) This prevents chemical reactions from occurring in the absence of the appropriate signal molecule. There are over 100 G-protein linked receptors. Although each is specific in function, they are closely related in structure. They are important in: genetic-gender reproduction neurotransmitters sensory reception (vision, taste and smell) embryonic development many hormone signals Many of the medicines in use today involve the mechanisms of G-proteins and is an active area of medical research.
Cell Communication - 10 Protein-Kinase Receptors Protein-kinase receptors are in the group of membrane proteins that have enzymatic activity. Tyrosine kinase receptors are common in animal cells. Serinethreonine kinases are also found. Protein kinases catalyze phosphorylation (using ATP) of a region of the receptor protein on the cytoplasmic side of the membrane when the signal molecule attaches to the surface. Relay proteins are then activated to elicit the appropriate cellular responses. Tyrosine kinase receptor molecules are pairs of small α helix chains of tyrosine attached to the inactive enzyme "tail" on the cytoplasmic side of the membrane, and to signal binding sites on the extracellular side of the membrane. Growth factors are typical signals for tyrosine kinase receptors. A signal molecule (ligand) attaching to the binding site of the tryosine kinase receptor triggers two tyrosine polypeptides to aggregate, forming a dimer. The dimer conformation promotes the phosphorylation of the tyrosine molecules of the opposite polypeptide in the dimer (using ATP). Each polypeptide is catalyzing the phosphorylation of the tyrosines of the opposite dimer component. The activated receptor is recognized by a number of relay proteins within the cell that undergo conformational changes when activated by the phosphorylated tyrosines. Multiple relay proteins can be activated at once so that a number of reactions can occur simultaneously within the cell. A multiple response is one of the primary differences between G-protein receptors and protein-kinase receptors. Some cancers may be caused by tyrosine-kinase receptors that aggregate (hence get phosphorylated) without the signal molecule.
Cell Communication - 11 Secondary Messengers, Pathways and Relay Proteins As you can see from the brief discussion so far, the transduction process (translation of a signal) often involves relays and pathways rather than a single action. Secondary messengers are important in relaying the message from the signal receptor within the cell. Pathways can provide more opportunities to coordinate and regulate cell activities and can also serve to amplify responses. The proteins involved in these pathways are called relay proteins because they are "relaying" the information from the signal to the target response. They also frequently serve to amplify the original signal to get a greater response. Secondary Messenger Molecules Small water-soluble molecules and ions can relay messages from the membrane proteins rapidly throughout the cytoplasm by diffusion. Relay substances work with both G-protein receptors and protein kinase receptors. Two of the most important secondary messengers are calcium ions and cyclic AMP. camp To provide an example of the use of camp as a secondary messenger, let's look at Earl Sutherland's work (the discover of the signal transduction pathway) on epinephrine as a signal that activates the conversion of glycogen to glucose-1- phosphate to rapidly process fuel molecules in response to stress situations. When epinephrine binds to its receptor G-protein, the response is an elevation in the concentration of cyclic AMP in the cell's cytosol. The G-protein receptor activates the plasma membrane enzyme, adenylyl cyclase which catalyzes the conversion of ATP to camp. The rapid increase in the concentration of camp activates a protein kinase pathway that ends in the conversion of glycogen to glucose-1-phosphate in the cell. Each step in the pathway activates an increasing number of molecules in the next step for a much greater total reaction in the end product. Looking at Sutherland's epinephrine example we see that a single epinephrine molecule attaching to a receptor protein in the plasma membrane can, because of the secondary messenger camp and the relay pathway, amplify the response a millionfold, bringing greater efficiency and timeliness in cell responses. (And when we are talking stress reaction, timeliness is important.)
Cell Communication - 12 camp works with a number of G-proteins and protein kinase receptors in cells, not just with epinephrine. In particular, camp activates a specific protein kinase, called protein-kinase A (which is a serine-threonine kinase). Protein-kinase A is an intermediate in a number of relay pathways in cells. As a feedback mechanism, camp is rapidly catalyzed to AMP, an inactive substance, in the absence of the signal molecule. The synthesis of camp can also be inhibited by a variety of molecules that block adenylyl cyclase (which prevents the synthesis of camp from ATP at the plasma membrane).
Cell Communication - 13 Ca ++ In animal cells, calcium ions are usually in a much higher concentration in the extracellular environment than within the cytosol. Within the cell, the ER serves as a Ca ++ reservoir. You will study the sarcoplasmic reticulum calcium reservoir needed for muscle contraction in Biology 202. Note: In humans, bone serves as a reservoir of calcium. Metabolic calcium needs take priority over structural needs. When calcium intake is low, calcium will be removed from bone to maintain appropriate blood (extracellular calcium) and cell calcium levels. Ca ++ often serves as a secondary messenger in the cytosol when its concentration is elevated by the actions of a signal molecule that results in the release of Ca ++ from the ER. As one would suspect by now, such activation requires a pathway and a number of molecules. A signal molecule binds to either a G-protein or a tyrosine-kinase receptor. The signal binding activates the membrane enzyme, phospholipase "C" which catalyzes the messenger inositol triphosphate (IP 3 ) derived from membrane phospholipids. Inositol triphosphate promotes the release of Ca ++ from the ER (by binding to a gated protein channel in the ER specific for Ca ++ ) Ca ++ then serves to activate any number of appropriate proteins to elicit cell responses, either by itself, or by binding to and activating the enzyme, calmodulin, which catalyzes or inhibits a number or relay protein kinase and protein phosphatase pathways in cells.
Cell Communication - 14 Relay Proteins Many signal transduction pathways use a sequence or relay to transmit the signal message within the cell. The typical mechanism for relay proteins to transmit information is phosphorylation of protein kinases. Relay proteins (which are protein kinases) catalyze the phosphorylation of two amino acids, threonine and serine, on their substrate proteins (the next relay protein in the pathway). Each phosphorylation causes a conformational change (the charged phosphate interacts with polar amino acids) in the substrate, activating it to catalyze the phosphorylation and conformational change of the next protein kinase in the pathway. Ultimately one reaches the end of the pathway, gets an active protein and appropriate cellular response. Relay Proteins Phosphorylation Cascade Although we associate the protein kinase relay pathways with a response in the cell that promotes a reaction, it is also important to note that the pathway can work to de-activate rather than activate, diminishing cell activity. That can be the appropriate response. Activity of protein kinases is also regulated by feedback mechanisms. A second set of proteins, the protein phosphatases, remove phosphates from protein kinases, stopping their activity. Protein phosphatases are active when the signal molecule for a protein kinase is absent, which shuts down that particular signal transduction pathway.
Cell Communication - 15 Amplification of the Response Amplification of response is common in both G-protein and Protein Kinase receptor signal transduction pathways. Using secondary messengers and relay pathways, a single signal molecule can effect a far greater response for more efficiency. Each step in the pathway triggers a greater number of molecules, for a cascading effect. Your text illustrates how signal amplification is accomplished with Rhodopsin, the G-protein-linked receptor important in vision. Each activated molecule in the relay triggers an ever increasing number of molecules so that the final relay is sufficient to send a message to the brain. Protein-kinase relays involving the cell-division promoting protein ras, are implicated in some cancers. A mutated ras becomes active all of the time, resulting in frequent, uncontrolled cell division.
Cell Communication - 16 Cellular Responses to Chemical Communication Signal Specificity We have seen in this discussion that chemical signaling involves 3 stages: reception, transduction and response. A number of times in discussing signal receptors and transduction we have alluded to the "appropriate response". The appropriate response may be a metabolic activity needed in the cell, a cell activity involving mechanical motion or rearrangement, active transport through a membrane via channel proteins, or regulating genetic activity by activating DNA molecules to initiate transcription and protein synthesis. Part of why chemical communication is so complex (and to some, confusing at this stage of one's education) is to ensure the appropriate responses. The specific receptor molecules in membranes and relay proteins within the cytosol determine the ultimate cellular response. This is important in many processes in organisms. Although all cells have the same DNA, not all DNA is active in any one cell. Receptor proteins in membranes have an impact on which genes ultimately get expressed in which cells, and whether a signal triggers an activation or an inhibition response. There are at least four categories of cell response to specific signals. A signal can attach to a receptor that triggers a transduction pathway leading to one response. A signal can attach to a receptor starting a pathway that branches into multiple transduction pathways leading to multiple responses In some cells, pathways interact. For example, two separate signals can trigger transduction pathways that interact with each other, either enhancing or inhibiting one response.
Cell Communication - 17 In different cells, the same signal molecule can elicit different responses by attaching to different receptors, each of which can activate different secondary messengers and relay pathways in different cells. For example, epinephrine does the following: Blood pressure Heart beat Insulin Blood glucose levels Oxygen consumption Release rbc from spleen reserve Blood flow to heart and skeletal network Blood flow to digestive system Dilate pupils Promote piloerection That one signal molecule can have such different effects on different cells and tissues explains the multiple symptoms of some diseases and disorders that are related to the "failure" of chemical communications. Several cancers are related to failure of chemical communication molecules to function properly. Many metabolic disorders and genetic disorders are related to the chemical communication sequences - receptor-transduction pathways and how they affect different cells and tissues. Some poisons affect signal receptors: Botulism, cholera and whooping cough involve bacterial toxins that inhibit G-protein-linked receptors. Cholera, for example, is caused by a toxin produced by the bacterium, Vibrio cholerae. The toxin prevents GTP from being hydrolyzed back to GDP on a G- protein receptor critical to maintaining water and salt balance in the intestine. The G-protein signal receptor stays active and camp levels remain high so water (and salts) flow into the intestine resulting in a serious loss of water and salts from the body. Although not emphasized in the discussion, the degradation of a signal molecule and secondary messenger molecules is just as critical to cell functioning as the signal. It is as important for cells to know when to stop as when to start a metabolic activity. Just as there are many alternatives to activation in chemical communication, there are methods of restoring the inactive molecular structures to await a new signal.