Cell Signaling and Communication - 1

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1 Cell Signaling and Communication - 1 Just as we communicate with other humans in a number of different ways, cells communicate with other cells and with their external environment with a set of cell signal mechanisms and process signal information in order to make appropriate responses within the cellular environment. Cellular communication is necessary to coordinate the myriad activities needed for any organism (unicellular or multicellular, prokaryote or eukaryote) to grow, develop and function. Most organisms use the same kinds of cell signaling mechanisms affirming again the uniformity of DNA for 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 within multicellular organisms, particularly in animals, is the focus of this section. To start our discussion, 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. Some myxobacteria aggregate to form a resistant colony, or fruiting body, when their nutrients are diminished. Nutrient deficient bacteria secrete a chemical into their environment that attracts others. Within the fruiting body, the cells produce thickened walls, forming resistant spores that withstand the poor environment. Myxobacteria Aggregating Fruiting Bodies Many protists and other unicellular organisms are similar in morphology. Gender is determined by genetic "mating types" and sexual reproduction requires individuals of different mating types to recognize each other in non-visual ways. Recognition is chemical. One individual recognizes an appropriate mate by secreting its chemical mating factor for which a compatible mate will have a receptor. The compatible mate will secrete its mating factor, for which the original cell has a receptor. These signals bind to the respective membrane receptors of the "mate" to trigger fusion of the two cells. Typically, once a zygote is formed, meiosis occurs and the new generation's haploid cells are formed. 50% will have one mating type, 50% the other.

2 Cell Signaling and Communication - 2 Receptiveness to sexual reproduction is a common use 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 as the female insect to trick an unsuspecting male insect into pollinating the orchid.) There are thousands of sexual selection examples involving chemical attractants. Chemicals released during mating may influence bonding and care of offspring in some organisms. Mate selection as an evolutionary process is discussed in Biology 212. Pollination strategies are a Biology 213 topic. Communication of Self In our discussions of membrane proteins we mentioned cell recognition proteins, important to the immune system. They play a critical role in communicating our identity to cells of our immune system and to our tissues. Each cell has unique surface identity markers. Many of these are glycolipds, glycoproteins or a group of proteins called MHC (major histocompatibility complex) proteins. The markers that form the human A, B and O blood groups are examples of identity markers. Most of the MHC proteins are immunoglobulins. A section of Biology 212 is devoted to discussion of the immune system and how it interacts with recognition markers. Signals and Receptor Proteins Our membrane discussion also mentioned the signal transduction or receptor proteins that have attachment sites for our chemical messenger molecules or signal molecules. 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. This sequence of cellular events is known as a signal transduction pathway, details of which we shall address in a bit. Not surprisingly, the typical cellular response to a signal is gene regulation or enzyme activity. Individual cells have different receptor proteins. This means that cells uniquely respond only to the signal molecules that are appropriate.

3 Cell Signaling and Communication - 3 Types of Cell Signaling Within multicellular organisms there are a number of types of cell signaling, usually categorized by the distance between the origin of the signal and the responding cell. Although it is tempting to categorize cell signals as being local or longdistance, as expected, there are more precise terms we can use: Autocrine Signaling Direct Contact Signaling Paracrine Signaling Synaptic Signaling Endocrine (Distance) Signaling Autocrine Signaling Intracellular Communication Cells can send intracellular signals that trigger receptors within their own membrane. Such signals often trigger differentiation in developmental processes. Direct Contact Signaling As discussed previously, gap junctions and plasmodesmata provide for metabolic cooperation between adjacent cells, and may help maintain homeostasis in connected cells for ion balance. Some signal molecules move through gap junctions. Hormone signals in plants move through plasmodesmata within tissues for more rapid responses. Recognition membrane proteins and other 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 adjacent cell receptors. For example, recognition markers are important in embryo develop as they signal adjacent cells to specialize for a specific tissue type and/or inhibit specialization. The mating types recognition in yeast previously mentioned is an example of direct contact signaling.

4 Cell Signaling and Communication - 4 Paracrine Signaling A short-lived signal molecule released by one cell that travels through the extracellular environment and acts on the receptor molecules of nearby cells is using paracrine signaling. When the signal reacts with its receptor molecule it is removed from the environment. Signal molecules that do not react are destroyed by extracellular enzymes. Growth factors in development are typical paracrine signal molecules. Synaptic Signaling A specialized paracrine signaling occurs with cells of the nervous system. 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 the neuromuscular junction). Neurotransmitter signal molecules and nerve function are discussed in Biology 212. Endocrine (Distance) Signaling Endocrine signaling involves chemicals produced in one cell or tissue that travel through the organism to their target cells and tissues. Many of these signal molecules are our regulatory hormones. Details of endocrine functions are discussed in Biology 212; growth regulators are included in Biology 213. The Signal Transduction Pathway 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. The mechanisms for chemical messaging that occur in yeasts, bacteria, plants and animals are remarkably similar, demonstrating the common genetic origins of communication. Appropriate receptor cells on the surface of the plasma membrane or within the cytoplasm of a cell induce changes in the cell that elicit an appropriate response, which is generally some type of chemical reaction or series of metabolic reactions. The three stages of cell signaling are, therefore, reception, transduction and response.

5 Cell Signaling and Communication - 5 The series of steps involved from signal reception to cell response is referred to as a signal transduction pathway. The kinds of responses vary depending on the signal and the target cell. Non-target cells will lack the appropriate receptors. The stages of chemical cell signaling: Reception The target cell must be able to detect that a signal is "arriving". The signal molecule must bind to a receptor molecule (usually a protein). The receptors are specific and specialized for different functions. Most receptor molecules are found on the cell surface, but there are also intracellular cytoplasmic receptors. Transduction - Initiating the Intracellular Signal The signal molecule binds to receptor molecule in a manner that brings about a change in the receptor molecule, which is typically a conformational change. This change effectively translates (or transduces) the signal into a form that the target cell can respond to. Transduction may be a single step or a relay (transduction) pathway of chemical reactions within the cell. o Intracellular Secondary Transduction In some cases, the initial receptor molecule's conformational change, rather than triggering the transduction pathway, activates a second molecule, called a secondary messenger. The secondary messenger then activates a transduction pathway for the appropriate cell response. A secondary messenger will often serve to amplify the initial signal for a greater response. Response and Responders The transduced receptor molecule (or secondary messenger) activates an appropriate response to the signal. Responders are molecules within the cell that perform or direct the performance of the appropriate cell activity. The response may be enzymatic activity, genetic transcription, movement of cytoskeletal components, synthesis of a structural molecule, or almost any cell activity. Cell signals ensure that the right kind of activity occurs in the cell at the right time and in the proper cell conditions. Let's look now at some specific details and examples of cell receptors and signal pathways.

6 Cell Signaling and Communication - 6 The Receptors A receptor can be located in the plasma membrane or within the cytoplasm of the cell. A signal molecule binds to a specific site on its receptor. Ligand is a term used to describe any (generally) small molecule that binds to a larger molecule. Signal molecules are 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. Many signal molecules are polar and their receptor molecules are found within the plasma membrane. Small nonpolar signal molecules, including many hormones and the gas, NO (nitric oxide), pass through the plasma membrane and have intracellular receptors. Binding of signal molecules to their receptors is reversible, and critical, since a signal molecule that remained attached to its receptor would be constantly activating the receptor. Although receptor molecules are specific to their signal molecules, inhibitors or antagonists can bind to receptors, blocking the receptor from functioning. Cytoplasmic (Intracellular) Receptors Cytoplasmic receptors function with small nonpolar signal molecules that can readily pass through the plasma membrane. The receptors may be in the cytoplasm or in the nucleus. Intracellular receptors are often enzymes or gene transcription factors. Gene Regulator Cytoplasmic Receptors Many of our steroid hormones function as signals for gene regulator receptors. These receptors have specific DNA binding sites that are normally not accessible for transcription in the nucleus. When activated by the signal molecule, the receptor complex is altered so it can function in the nucleus as a transcription factor to initiate gene activity.

7 Cell Signaling and Communication - 7 Cytoplasmic Enzyme 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". Many of our digestive enzymes are produced in inactive forms and must be activated by signal molecules in the target location of the digestive system. Nitric oxide (NO), which functions to relax smooth muscle tissue, is an enzyme signal molecule. Plasma Membrane Receptors A signal molecule that has a plasma membrane receptor will have a shape that fits into a portion of its receptor protein, which is an integral protein, in the plasma membrane. The signal transduction is 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, the responder, or an aggregation of receptor proteins, or activates a series (or relay) of molecular interactions leading to a cellular response. In some cases, the ligand (signal molecule) promotes an aggregation of receptor proteins in the plasma membrane. There are a number of different types of plasma membrane receptors involved in signaling. The three most common in animals and higher plants are: Ion-Channel Receptors Protein-Kinase Receptors (typically tyrosine-kinases in animals) G-protein (Guanine-protein) Coupled Receptors Ion-Channel Receptors As discussed previously, ion channels are gated protein pores in the plasma membrane that open and close in response to signals. The pores are highly specific and allow the flow of a specific 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 cell reaction or relay reactions. Ligand binds, channel opens, Ligand dissociates, Ligand released ions flow through channel closes

8 Cell Signaling and Communication - 8 Protein Kinase Receptors Protein kinase receptors are in a group of proteins that have enzymatic activity. A kinase is a phosphorylating enzyme that catalyzes transferring phosphates from ATP to some specific protein. Phosphorylating supplies energy. Tyrosine kinase membrane receptors are common in animal cells. Serine and threonine kinases are also found in the cytoplasm of cells. Protein kinase receptors catalyze phosphorylation of a region of the receptor protein when the signal molecule attaches to its surface. Relay proteins (often protein kinases themselves) are then activated to elicit the appropriate cellular responses. Protein phosphatase enzymes remove the phosphate molecules to de-activate the kinase relay molecules to turn off the pathway. The phosphatase and kinase balance acts like an on-off switch for cellular pathways that rely on phosphorylations. The tyrosine kinase receptor molecule consists of small 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. When a signal molecule attaches to the binding site of its tryosine kinase receptor it 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. 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. The ability to elicit multiple responses is a characteristic of the protein-kinase receptors. About 2% of human genes code for protein kinases. Our cells may have hundreds of different protein kinases. Insulin is a protein kinase signal molecule as are many growth factors. The cyclin-cdk complex signals for cell division involve protein kinase receptors. Some cancers may be caused by tyrosine-kinase receptors that aggregate (hence get phosphorylated) without their signal molecule, or by a defective phosphatase that may keep a relay continually phosphorylated (active).

9 Cell Signaling and Communication - 9 G-Protein Coupled Receptors There are a number of membrane receptor molecules that work with a special group of helper proteins called G-proteins (guanine-proteins). The membrane receptor proteins that work with G-proteins have a common structure. Each is comprised of 7 helices (a motif) within the membrane, an attachment site for the G-protein on the cytoplasmic side and an attachment site for the signal molecule on the extracellular side of the membrane. How G-Proteins Work G-proteins are intermediates in cell signal pathways between receptor molecules and target molecules, which are often enzymes. In their non-active form, G- proteins have guanine diphosphate (GDP) attached. The active form of a G-protein has guanine triphosphate (GTP). ATP is used to phosphorylate GDP to form GTP. G-proteins also have a binding site for the receptor protein in the plasma membrane and to an effector protein for the transduction path to effect a cellular response. A ligand attaching to the receptor molecule triggers (by inducing a conformational change in) the receptor molecule to bind to its associated G-protein. The receptor- G-protein complex triggers GTP to displace the inactive GDP on the G-protein. The signal then dissociates from the receptor. In general, a portion of the activated G-protein then migrates along the membrane and binds to a specific effector protein, typically an enzyme or an ion channel in the membrane. The activated effector initiates a signal pathway in the cell resulting in a specific cell response. The cellular response may be an activation or an inhibition.

10 Cell Signaling and Communication - 10 GTP activation is short-term. Once the G-protein activates its effector protein, GTP is hydrolyzed to GDP inactivating the G-protein and the G-protein subunits are re-associated to be ready to activate again. The GTP hydrolysis back to GDP in the cell is catalyzed by the GTPase 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. Different subunits of the same G- protein may respond to the same signal in different tissues eliciting an activation in one tissue and an inhibition in a second, as in the response in different tissues to epinephrine, a stress (fight or flee) signal molecule. G-proteins are important in: genetic-gender reproduction neurotransmitter function sensory reception (vision, taste and smell) embryonic development hormone signaling G-protein coupled receptors function in our sense of smell Some poisons affect signal receptors: Botulism, cholera and whooping cough toxins inhibit G-protein-linked receptors. Cholera toxin blocks the GTP GDP hydrolysis of a G-protein involved with salt and water balance in the intestine so cells secrete large amounts of water and electrolytes. As much as 60% of medicines in use today involve the mechanisms of G-proteins.

11 Cell Signaling and Communication - 11 Signal Transduction: Secondary Messengers, Pathways, Relay Proteins and the Phosphorylation Cascade Signal transduction would be easy if each signal molecule had a receptor that caused a direct cell response. Such interactions between the signal and receptor in which the receptor causes the response are known as direct transduction. However, the transduction process (translation of a signal) is more commonly an indirect transduction, involving cytoplasmic secondary messengers that mediate added steps in the transduction. Direct Signal Transduction Indirect Signal Transduction Both direct and indirect transduction, with a secondary messenger involved, can result in a cascade of steps, or transduction relays. 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. We will discuss both relay proteins and secondary messengers in this section. Relay Proteins The Protein Kinase Phosphoryation Cascade Many signal transduction pathways use a sequence of steps (or relay) to transmit the signal message within the cell. The typical relay proteins are protein kinases (recall that a kinase is an enzyme that phosphorylates its substrate) that catalyze the phosphorylation of two amino acids, threonine and serine, on the next relay protein in the cascade, which in turn phosphorylates the next protein in the relay. Each protein in the cascade, when phosphorylated, catalyzes the next. Ultimately one reaches the end of the pathway, or a branch in the pathway, for an appropriate cellular response. Each cascade can amplify and communicate the needed signal until the final target is reached. With different target proteins within the cascade, variable responses are also possible with phosphorylation cascades. The protein kinase receptors are typically involved in direct transduction activating a phosphorylation relay (or cascade) because the receptor, once phosphorylated transfers its phosphate to the first protein in the relay.

12 Cell Signaling and Communication - 12 Relay Proteins Phosphorylation Cascade Protein-kinase cascades are common in growth and development activities and are often activated by growth factors. One protein-kinase relay involving the celldivision promoting protein ras, is implicated in a number of cancers. A mutated ras becomes permanently attached to GTP, so that the cascade is active all of the time, resulting in the frequent, uncontrolled cell division of cancers. (We will discuss gene regulation, cell division controls and cancer later.) 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. Protein kinase activity is 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.

13 Cell Signaling and Communication - 13 Secondary (Second) Messenger Molecules Membrane proteins are primary receptors for signal molecules, but many receptors require additional molecules in the cytoplasm in order to relay their message. Small water-soluble molecules and ions can relay messages from the membrane proteins rapidly throughout the cytoplasm by diffusion. These relay molecules, called secondary (or second) messengers, work with both G-protein receptors and protein kinase receptors. Cyclic adenosine monophosphate (camp), calcium ions (Ca ++ ) and Nitric oxide (NO) are important second messengers in cells. In addition, the hydrolysis of the phospholipid, phosphatidyl inositol-bis-phosphate, PIP2, forms two second messengers, IP 3 and DAG, (inositol triphosphate and diacylglycerol) which work with Ca ++. c A M P Earl Sutherland (the discover of the signal transduction pathway) was the first to determine that secondary messenger molecules were often required. His research was on epinephrine, the hormone that activates the stress responses in cells and tissues known as "fight or flee". In liver cells, epinephrine activates the liver enzyme that catalyzes the rapid conversion of glycogen to glucose-1-phosphate but only when sufficient camp is present. A single epinephrine molecule attaches to a G-protein receptor in the plasma membrane that activates the enzyme, adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to camp, which triggers a protein kinase cascade. This relay pathway can amplify the response a million fold, bringing greater efficiency and timeliness in cell responses. (And when we are talking stress reaction, timeliness is important.) Conversion of ATP camp Conversion of camp AMP 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, preventing the synthesis of camp from ATP at the plasma membrane, hence inhibiting certain cell activities.

14 Cell Signaling and Communication - 14 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 serinethreonine kinase). Protein-kinase A is an intermediate in a number of relay pathways in cells. camp also activates ion channel targets. The importance of cyclic AMP and its role with G-protein coupled signaling has led to research in medicine and health with diseases and medical conditions that activate or inhibit G-proteins that use cyclic AMP secondary messaging. I P 3 and DAG: Lipid-Derived Secondary Messengers A signal molecule that may bind to either a G-protein or a tyrosine-kinase receptor can activate the activate the membrane enzyme, phospholipase "C" to catalyze the hydrolysis of the membrane phospholipid, phosphatidyl inositol-bisphosphate, PIP2, to form two secondary messengers, IP 3 and DAG. IP 3 is released into the cytosol. DAG remains in the membrane. DAG, and IP 3 often work cooperatively with a third secondary messenger, Ca ++. IP 3 typically promotes the release of Ca ++ from the ER by binding to a gated protein channel in the ER specific for Ca ++. DAG and Ca ++ together activate the membrane enzyme, PKC (protein kinase "C"). PKC, which is actually a group of related kinases) serves to activate any number of appropriate proteins to elicit cell responses.

15 Cell Signaling and Communication - 15 C a + + as a Secondary Messenger In animal cells, calcium ions are usually in a much higher concentration in the extracellular environment than within the cytosol. Within the cell, the endoplasmic reticulum serves as a Ca ++ reservoir. Ca ++ pumps are used to maintain this gradient by pumping Ca ++ out of the cell and/or from the cytosol into the ER and some other organelles. Ca ++ serves as a second messenger in the cytosol when its concentration is elevated. As discussed above, Ca ++ is released from the ER to serve as a secondary messenger when activated by IP 3 and works cooperatively with DAG. Muscle contraction, cell division and chlorophyll synthesis are three important cell activities that use Ca ++ as a second messenger. Activation of Ca ++ secondary messenger Role of Ca ++ in Development Independently of its cooperative role with IP 3 and DAG, Ca ++ can activate ion channels, including Ca ++ ion channels, as well as promote exocytosis. Sperm penetration activates Ca ++ ion channels in egg cells to signal successful fertilization. Ca ++ also activates a Calcium-binding protein, calmodulin, which catalyzes or inhibits a number of protein kinase and protein phosphatase pathways in cells. For example, calmodulin activates the protein kinase relay that phosphorylates myosin in muscle contraction.

16 Cell Signaling and Communication - 16 Nitric Oxide (NO) and Cyclic GMP (Guanine Monophosphate) The gas, nitric oxide (NO) is an intermediate messenger molecule that leads to blood vessel dilation by promoting the relaxation of the smooth muscle layer. NO is synthesized in smooth muscle cells when a primary signal, acetylcholine, binds to its receptor, a reaction that promotes Ca ++ release through IP 3 -DAG activation. Ca ++ then activates the enzyme, NO synthase that converts arginine to NO. NO binds to an enzyme that catalyzes synthesis of cyclic guanosine monophosphate (cgmp), a molecule that effects a number of cell-specific responses, one of which is relaxation of smooth muscle tissue in blood vessels increasing blood flow. NO is an unstable gas, and degrades rapidly. The discovery of NO as a secondary messenger helped explain how nitroglycerin can help relieve angina symptoms in people with cardiovascular disease. The drugs Viagra and Cialis prevent the hydrolysis of cgmp to GMP, keeping the signal pathway active, which maintains an increased arterial blood flow. Such drugs were originally being researched as cardiovascular medications.

17 Cell Signaling and Communication - 17 Signal Amplification The often-elaborate G-protein and protein kinase signal transduction pathways serve to amplify cellular responses. Using secondary messengers and relay pathways to amplify a response, 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. The visual pigment, rhodopsin, a G-protein-linked receptor important in vision, undergoes signal amplification. 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. The amplification of glucose uptake in cells in response to the effect of an epinephrine signal molecule is similar. Amplification of Rhodopsin Glucose Uptake Amplification

18 Cell Signaling and Communication - 18 Signal Efficiency Proteins are large molecules and transduction pathways work in the cytoplasm. Although small secondary messenger molecules may diffuse rapidly, large proteins do not. Cells may have scaffolding proteins that can bind to both an activated membrane receptor and a set of protein kinases to facilitate more rapid transduction. Some brain cells have permanent scaffolding protein protein kinase networks. Proteins that function in multiple pathways also provide for greater efficiency. A relay with intersections and branches can do multiple functions. Unfortunately, this can also be problematic if a critical relay protein is defective. Such defective receptors or relay proteins explain some of the multiple effects of some genetic disorders. Signal Specificity and Cell Response 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, particularly transcription. In part, the complexity of chemical communication is to ensure the appropriate change in cell function in response to any given signal. Cell Metabolism Signal Response Gene Transcription Signal Response

19 Cell Signaling and Communication - 19 Signal Specificity The specific receptor molecules in membranes and relay proteins within the cytosol determine the ultimate cellular response, with multiple opportunities for cell regulation and control. This is important in many processes in organisms. Although all cells have the same DNA, not all DNA is active in any one cell. The variety of receptor proteins found in different cells have an impact on which genes ultimately get expressed in which cells, and whether a signal triggers an activation or an inhibition response in any given cell. For example: For example, epinephrine does the following: Blood pressure Heart beat Blood glucose levels Oxygen consumption Blood flow to heart and skeletal network Insulin Blood flow to digestive system Release rbc from spleen reserve Dilate pupils 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. Some cancers are related to chemical communication molecules that fail to function properly. Many metabolic and genetic disorders are related to chemical communication signal transduction pathways and how they affect different cells and tissues. Signal Regulation Although not emphasized in the discussion of types of signal transduction pathways, the termination of a signal molecule and secondary messenger molecules is just as critical to cell functioning as the signal. All cell activities are regulated. It is as important for cells to know when to stop as when to start a metabolic activity. As seen with the example of the G-protein Ras and cancer, failure to terminate a signal can have serious impacts. 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. Signal termination doesn t just stop a signal transduction pathway, but also prepares the cell for a new signal. Regulating signal transduction has many facets: The rate at which the signal molecule or any of the transduction pathway proteins are degraded affects the response. The concentration of an intermediary or target molecule, such as amount of NO synthesized affects the cell response Ca++ release from ER is regulated by both secondary messengers and ion pumps. The enzyme phosphodiesterase converts camp to AMP to stop the GTPase activity of G-proteins Protein phosphatase enzymes inactivate protein kinase relays.

20 Cell Signaling and Communication - 20 A Summary of Cell Communications