Syllabus

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Chapter 11. Cell Communication.

• An overview of cell signaling.

– Cell signaling evolved early in the history of life.

– Communicating cells may be close together or far apart.

– The three stages of cell signaling are receptiontransduction and response.

• Signal Reception and the Initiation of Transduction.

– A signal molecule binds to a receptor protein causing the protein to change shape.

– Most signal receptors are plasma membrane proteins.

• Signal Transduction Pathways.

– Pathways relay signals from receptors to cellular responses.

– Protein phosphorylation, a common mode of regulation in cells is a major mechanism of signal transduction.

– Certain small molecules are key components of signaling pathways (second messengers).

• Cellular responses to signals.

– In response to a signal a cell may regulate activities in the cytoplasm or transcription in the nucleus.

– Elaborate pathways amplify and specify the cell’s response to signals.

• An Overview of Cell Signaling.

– Cell signaling evolved early in the history of life.

• One topic of cell conversation is “sex”.

– Research has found that the yeast Saccharomyces cerevisiae identify mates via chemical signaling (Fig 11.1).

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– Cells of mating type a secrete a chemical signal called a factor, while a cells secrete a factor.

» These factors bind to receptors on the opposite cell type.

» The interaction of factor and receptor cause the cells to grow towards each other without the factor actually entering the cell.

» The cells eventually fuse (fusion or mating) combines the genes of the separate cells.

– How does the mating signal at the yeast cell surface bring about a cellular response?

» The process by which a signal on the cell surface is converted into a specific cellular response is a series of steps called a signal-transduction pathway (STP).

– Many STPs exist and have been studied in yeast and mammals, furthermore they have been found to be strikingly similar (also similarities in plants and bacteria). Indicates?

»

– Communicating cells may be close together or far apart (Fig 11.3).

• Local regulators are used by a multicellular organisms cells to influence cells in the vicinity.

– Paracrine signaling involves releasing molecules into the extracellular space to influence many cells in the area.

– Synaptic signaling (used in the nervous system) uses a neurotransmitter released into a synapse, the narrow space between the transmitting cell and the target cell.

• Plants and animals use hormones for long-distance signaling.

– Specialized endocrine cells secrete hormones into bodily fluid (Ex: blood or other vessels).

• Cells may also communicate by direct contact through cell junctions or cell-cell recognition (Fig 11.4).

– The three stages of cell signaling are reception, transduction and response.

• Earl W. Sutherland and his colleagues at Vanderbilt Univ. were pioneers in research leading to our current understanding of how chemical messengers act via signal-transduction pathways (Nobel Prize 1971).

– Studied how the animal hormone epinephrine stimulated glycogen (storage carbohydrate) breakdown.

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– They found that intact cells were necessary for epinephrine to act and that the cell’s plasma membrane was somehow involved.

• Sutherland’s early work indicated the process going on at the receiving end of a cellular conversation can be dissected into three stages: Reception, transduction and response.

– Reception: Is the targets cell’s detection of an incoming signal; detection is usually via the signal binding to a protein (receptor) at the target cell’s surface.

– Transduction: Binding of the signal molecule changes the receptor protein in some way; the transduction stage converts the signal to a form that can cause a cellular response (often occurs over multiple steps, a signal-transduction pathway).

– Response: Transduced signal triggers a cellular response, could be any imaginable cellular process (Ex: ?).

• Signal Reception and the Initiation of Transduction.

– Signal receptors act as identity tags on cells so that only intended target cells will “hear” the message (chemical).

– A signal molecule binds to a receptor protein, causing the protein to change shape.

• A receptor has a specific shape that is complementary in shape to a specific signal molecule.

• Binding of the signal molecule (ligand binding) to the receptor (lock and key) causes the receptor to undergo a change in conformation (shape).

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– The shape change often directly activates the receptor to interact with another molecule often inside or associated with the target cell.

– Most signal receptors are plasma membrane proteins.

• Most signal molecules are are water soluble and too large to pass easily through the plasma membrane.

• Like yeast mating factors most signal molecules bind specific sites on receptor proteins that are embedded in the cell’s plasma membrane.

• Such a receptor transmits information from the extracellular to intracellular environments by changing shape or interacting with other molecules.

• Three major types: G-protein-linked receptors, tyrosine-kinase receptors and ion-channel receptors.

• G-protein-linked receptors are plasma membrane receptors that work with the help of a protein called a G protein.

– Examples include yeast mating factor receptors, epinephrine receptor and other hormone and neurotransmitter receptors.

• Although G proteins have many different receptors for different signals they each have seven a helices spanning the membrane (Fig 11.6).

• The G protein is loosely attached to the cytoplasmic side of the membrane.

– The G protein functions as a switch that is on or off depending on which of two guanine nucleotides are attached (GTP on, GDP off).

– Function (Fig 11.7):

» 1)

» 2) Causes G protein to bind a GTP displacing GDP, G protein is active.

» 3) G protein binds another protein, usually an enzyme activating it.

» 4) This activated enzyme can trigger the next step in the pathway.

• Tyrosine-kinase receptors (TKR) are important for activating more than one signal at one time.

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– These receptors have their own enzymatic activity, they act as a tyrosine-kinase.

» A tyrosine-kinase transfers a phosphate group from ATP to the amino acid tyrosine on a substrate protein.

– TKR often have only a single a-helix spanning the membrane and an intracellular tail containing a number of tyrosine residues.

– Receptor Activation occurs in two steps (Fig 11.8):

» 1) Ligand binds and causes two receptors to aggregate forming a dimer.

» 2) Aggregation activates the tyrosine-kinase portions of both receptors and they then add phosphates to the other tails tyrosines (receptor is now fully activated).

» 3) Relay proteins then bind the phosphorylated tyrosines and are activated (10+ may be activated).

» 4) These activated relay proteins may trigger many different transduction pathways and cellular responses.

• Some membrane receptors of chemical signals are ligand-gated ion channel which are pores that open or close in response to a chemical signal (Fig 11.9).

– This allows the entrance or blocks the entrance of ions like Na⁺ or Ca²⁺.

» These channel proteins bind a signal molecule as a ligand which leads to a shape change and immediately allows ions to move in or out.

» Often immediately changes cell function (Ex: electrical impulses of the nervous system).

• Intracellular receptors are not membrane proteins but can be dissolved in the cytosol or nucleus of target cells.

– The chemical messenger must be able to pass through the target cell membrane to reach these receptors.

»

– One example: Testosterone travels through the blood and enters cells throughout the body, target cells contain receptor molecules for testosterone in their cytoplasm.

– The hormone-receptor complex enters the nucleus and turns on specific genes that control male sex characteristics.

• Signal Transduction Pathways.

– Signal transduction is often a multistep process, which often amplifies the signal leading to a large cellular response.

– Pathways provide more opportunities for coordination and regulation that simpler systems do.

– Pathways relay signals from receptors to cellular responses.

• Signal-transduction pathways act like falling dominoes, the activated receptor activates another protein which in turn activates another and so on until the protein pathway produces the final cellular response.

– Remember the original chemical signal often never even enters the cell it usually just activates the receptor.

» Often this activation, conformational change is brought about by phosphorylation.

– Protein Phosphorylation, a common mode of regulation in cells, is a major mechanism of signal transduction.

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• The general name for a protein that transfers a phosphate from ATP to a protein is a protein kinase.

– Cytoplasmic kinases act most often on other proteins not themselves also often phosphorylate serine or threonine residues not tyrosine (unlike receptor kinases).

– Many of the relay molecules in a signal-transduction pathway are kinases, and often act in concert (Fig 11.11).

» Ex: Fig. 11.11 is similar to that used by yeast mating factors.

– Phosphorylation often activates proteins (enzymes), however, in some cases it also can deactivate proteins.

» Importance: A full 1% of all our genes are thought to be kinases and are frequently indicted in causing cancer when they are out of control.

– The cell must also be able to turn off the signal (turning off the signal-transduction pathway), this is carried out by the protein phosphatases.

» Protein phosphatases can rapidly remove phosphates from a protein deactivating them, these predominate over kinases when there is no chemical signal.

– Certain small molecules and ions are key components of signaling pathways (second messengers).

• Not all components of STPs are proteins some are small molecules or ions, called second messengers.

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• Second messengers are water soluble and therefore can rapidly spread throughout the cell by diffusion, the two most common are Ca²⁺ and cyclic AMP (cAMP; Fig 11.12).

• Sutherland coined the term second messenger and wanted to find the second messenger for epinephrine-mediated glycogen breakdown.

– He found cyclic adenosine monophosphate or cyclic AMP.

– A transmembrane protein enzyme adenylyl cyclase converts ATP to cAMP (Fig 11.12 and 11.13).

– cAMP activates protein kinase A and the pathway continues from there.

» Often associated with G-protein-coupled receptors.

»

• Calcium ions and inositol triphosphate.

– Many signal molecules (Ex: neurotransmitters and growth factors) increase the intracellular concentration of Ca²⁺.

– Increasing the Ca²⁺ concentration inside of cells can cause many responses: Muscle cell contraction, cell secretion of certain substances, and cell division.

– Ca²⁺ is actively pumped out of the cell and also into the ER, and sometimes the chloroplast and mitochondria (Fig 11.14).

» Therefore the Ca²⁺ concentration is much higher in the blood and ER than in the cytoplasm of the cell.

– In response to a chemical signal the cytosolic Ca²⁺ concentration may rise, by Ca²⁺ from the ER.

– The pathway leading to Ca²⁺ release involves other second messengers diacylglycerol (DAG) and inositol triphosphate (IP₃).

» Ca²⁺ acts after IP₃ so it could be considered a “third messenger”.

– Calcium often functions with the help of the protein calmodulin, which binds calcium and mediates calcium-regulated processes within the cell.

• Cellular Responses to Signals.

– In response to a signal, a cell may regulate activities in the cytoplasm or transcription in the nucleus.

• Ultimately a signal-transduction pathway leads to the regulation of one or more cellular activities (Ex: change in metabolism or opening or closing a channel protein).

– Ex: final step of epinephrine-mediated glycogen breakdown pathway is the activation of the enzyme that catalyzes glycogen breakdown.

• Many other signaling pathways regulate not the activity of enzymes but the synthesis of the enzyme (Fig 11.17).

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– Ex: the steroid receptor acts as a transcription factor activating gene expression in the nucleus.

» Transcription factors are proteins involved in controlling the rate of transcription for a particular gene or genes.

– Elaborate pathways amplify and specify the cell’s response to signals.

• Signaling pathways with their multiple steps do two things amplify the signal and add to the specificity of response (Fig 11.18).

• Signal amplification occurs due to elaborate enzyme cascades in response to a signal.

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(Fig 11.16).

» Ex: epinephrine-induced glycogen breakdown starts with one receptor ends with 10⁸ molecules of glucose-1-phosphate.

• The specificity of cell signaling (Fig 11.18) is important because for example your liver and heart cells are all exposed to blood (and therefore hormones) but you only want one of them to respond to certain hormones or perhaps respond differently to a signal ( Ex: epinephrine at the liver and heart).

– How this occurs is due to the different collections of proteins, including receptors, that cells have.

» Ex: depending on the proteins available to respond to epinephrine the cell will have a different response.

• Figure 11.18 shows simplified examples (few relay molecules) signal-transduction pathways are complex and often have many steps.

– Since the cell’s cytosol is large in comparison to the protein’s size it would be inefficient to use diffusion for interactions between members of a pathway instead evidence suggests scaffolding proteins (Fig 11.19).

» Scaffolding proteins bring one or more relay molecules into the vicinity of an activated receptor or other activated relay molecule.

• Importance: Abnormal relay proteins can lead to disorders.

– Ex: Defective or missing relay protein(s) can lead to the inherited disorder Wiskott-Aldrich syndrome (WAS) which can cause abnormal bleeding, eczema and a predisposition to infection and leukemia.

• An important thing to keep in mind is that the mechanisms shown in figure 11.18 also have inhibitory mechanisms in many instances, signal transduction is a tightly regulated process.

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