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Campbell Chapter 11 - Cell Communication
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Introduction to cell signaling and communication
Cells can signal to each other and interpret signals from the environment
Chemical signals are the most common form of communication
Example of flight response triggered by epinephrine
Cell signaling mechanisms are evolutionarily conserved across species
Focus on mechanisms of receiving, processing, and responding to chemical signals
Introduction to apoptosis as a mechanism of programmed cell death
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Signal transduction pathway in yeast and animal cells
Similarities in molecular details of signal transduction between yeasts and mammals
Signaling mechanisms evolved in ancient prokaryotes and single-celled eukaryotes
Cell signaling is critical among prokaryotes, such as bacterial quorum sensing
Communication among microorganisms, using yeast as an example
Genetic engineering of yeast cells to alter receptors and mating factors
Importance of unique match between mating factor and receptor in ensuring mating only among cells of the same species
Communication among bacteria through chemical signals for nutrient availability and coordination of behaviors
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Skin wounds can become infected and deadly if infected with antibiotic-resistant bacteria
MRSA (methicillin-resistant Staphylococcus aureus) is a strain of antibiotic-resistant bacteria
Quorum sensing is the mechanism by which cells sense their own population density
Two synthetic peptides, peptides 1 and 2, have been proposed to interfere with the S. aureus quorum-sensing pathways
Experiment involves growing four cultures of S. aureus and measuring toxin concentration in each culture
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Biofilms are aggregations of bacterial cells adhered to a surface
Bacterial biofilms can cause cavities and gum disease
Quorum sensing is involved in the secretion of toxins by infectious bacteria
Interfering with quorum sensing pathways can be an alternative treatment for antibiotic-resistant infections
Cells in a multicellular organism communicate via signaling molecules
Local signaling can occur through direct contact or secretion of signaling molecules
Paracrine signaling is a type of local signaling where molecules travel short distances
Hormonal signaling is a type of long-distance signaling where hormones are secreted into body fluids
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Sutherland and his colleagues were investigating how epinephrine triggers the "fight-or-flight" response in animals
Epinephrine stimulates the breakdown of glycogen in liver cells and skeletal muscle cells
Glycogen breakdown releases glucose 1-phosphate, which can be converted to glucose 6-phosphate for energy production
Epinephrine mobilizes fuel reserves in the body
Epinephrine activates the enzyme glycogen phosphorylase, which is responsible for glycogen breakdown
Epinephrine can only activate glycogen phosphorylase when added to intact cells
Reception, transduction, and response are the three stages of cellular communication
Reception:
Reception is the target cell's detection of a signaling molecule from outside the cell
Signaling molecules bind to receptor proteins located at the cell's surface or inside the cell
Epinephrine binds to a receptor protein in the cell
Transduction:
The binding of the signaling molecule changes the receptor protein, initiating a series of steps
The signal is transduced inside the cell before the cell can respond
Response:
The final molecule in the transduction pathway triggers the cell's response
In Sutherland's experiment, the response is the activation of glycogen phosphorylase
Cell Signaling:
Animals and plants use different types of signaling molecules for communication
Local signaling occurs between adjacent cells
Synaptic signaling occurs in the animal nervous system
Hormonal signaling occurs in animals and plants
Hormones travel via the circulatory system to reach target cells
The ability of a cell to respond to a signaling molecule depends on whether it has a specific receptor molecule
The signal must be transduced inside the cell before the cell can respond
Diagram of Cell Signaling:
The diagram shows an overview of cell signaling
Signal reception occurs at the plasma membrane
Signal transduction involves a pathway of several steps, with each relay molecule bringing about a change in the next molecule
The final molecule in the pathway triggers the cell's response
Epinephrine would fit into the diagram at the reception stage, where it binds to a receptor protein at the plasma membrane.
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Ligand binding causes a receptor protein to undergo a change in shape
This shape change can activate the receptor or cause the aggregation of multiple receptor proteins
Most signal receptors are plasma membrane proteins, but some are located inside the cell
Cell-surface transmembrane receptors play crucial roles in biological systems
The largest family of human cell-surface receptors is the G protein-coupled receptors (GPCRs)
GPCRs are targeted by drugs such as maraviroc for treating AIDS
Water-soluble signaling molecules bind to specific sites on transmembrane receptor proteins
Three major types of cell-surface transmembrane receptors are GPCRs, receptor tyrosine kinases, and ion channel receptors
Reception process of transduction converts the signal to a form that can bring about a specific cellular response
Transduction often occurs in a sequence of changes in different molecules, known as a signal transduction pathway
The third stage of cell signaling is the response, where the transduced signal triggers a specific cellular response
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G protein-coupled receptors (GPCRs) are cell-surface transmembrane receptors that work with the help of G proteins
GPCRs are a large family of eukaryotic receptor proteins with a secondary structure of seven transmembrane α helices
GPCR-based signaling systems are widespread and diverse in their functions
Malfunctions of associated G proteins are involved in many human diseases
Binding of signaling molecules to GPCRs activates the receptor and changes its shape
The activated receptor binds to an inactive G protein, causing a GTP to displace the GDP and activate the G protein
The activated G protein can then bind to an enzyme and trigger a cellular response
The changes in the enzyme and G protein are temporary, as the G protein eventually hydrolyzes its bound GTP to GDP and becomes inactive again
The G protein can be reused due to its GTPase function, allowing the pathway to shut down
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Tyrosine kinases (RTKs) are a major class of cell surface receptors characterized by having enzymatic activity.
RTKs are protein kinases that transfer phosphate groups from ATP to other proteins.
RTKs specifically transfer phosphate groups to tyrosines of substrate proteins.
RTKs can activate multiple transduction pathways and cellular responses upon binding a ligand.
Abnormal RTKs are associated with various types of cancer.
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Malfunctions of cell-surface receptors are associated with human diseases such as cancer, heart disease, and asthma.
Determining the structures of cell-surface receptors has been challenging due to their flexibility and instability.
Abnormal functioning of RTKs is associated with certain types of cancer, and targeted therapies like Herceptin have been developed to inhibit cell division.
Intracellular receptor proteins are found in the cytoplasm or nucleus of target cells and can be activated by hydrophobic signaling molecules or small molecules like nitric oxide.
Ligand-gated ion channels are membrane channel receptors that open or close in response to ligand binding, allowing or blocking the flow of specific ions.
Ligand-gated ion channels are important in the nervous system for transmitting electrical signals between nerve cells.
Some ion channels are controlled by electrical signals instead of ligands and are crucial for nervous system function.
Question:
The flow of ions through a ligand-gated channel is an example of passive transport.
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Cell communication involves the activation of receptor proteins by hormones
Hormone-receptor complex enters the nucleus and turns on specific genes
Genes are transcribed into mRNA by transcription factors
Aldosterone receptor acts as a transcription factor
Intracellular receptors function in a similar way
Cell-surface receptor protein is not required for steroid hormones to enter the cell
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Transduction stage of cell signaling is a multistep pathway
Multiple steps amplify the signal and provide coordination and control
Signal transduction pathway involves relay molecules that activate each other
Protein kinases phosphorylate proteins in a phosphorylation cascade
Phosphorylation causes shape changes in proteins, activating or deactivating them
Protein kinases regulate the activity of many proteins in a cell
Signal is relayed along the pathway through shape changes and phosphorylation
Protein phosphorylation and dephosphorylation regulate protein activity
Protein kinases transfer phosphate groups to proteins, while phosphatases remove them
Note: This transcript provides information about cell communication, the role of receptor proteins, the activation of genes, the function of transcription factors, the process of signal transduction, the involvement of protein kinases in phosphorylation cascades, and the regulation of protein activity through phosphorylation and dephosphorylation.
Page 12: Cell Communication
Cyclic AMP as a Second Messenger
Earl Sutherland discovered that epinephrine causes glycogen breakdown within cells
Sutherland searched for a second messenger that transmits the signal from the plasma membrane to the cytoplasmic machinery
Binding of epinephrine to the plasma membrane elevates the cytosolic concentration of cyclic AMP (cAMP)
Adenylyl cyclase converts ATP to cAMP in response to epinephrine
G protein-coupled receptors activate adenylyl cyclase, leading to the synthesis of cAMP
cAMP broadcasts the signal to the cytoplasm
Phosphodiesterase converts cAMP to AMP, requiring another surge of epinephrine to boost cAMP concentration again
Activation of Adenylyl Cyclase and Formation of cAMP
Epinephrine and other signaling molecules activate adenylyl cyclase by G proteins and formation of cAMP
Elevated cAMP levels activate protein kinase A, which phosphorylates various other proteins
Abnormal activity of protein kinase A can cause abnormal cell division and contribute to cancer development
Protein phosphatases dephosphorylate and inactivate protein kinases, turning off the signal transduction pathway
Phosphatases make protein kinases available for reuse, enabling the cell to respond to extracellular signals
Phosphorylation-dephosphorylation system acts as a molecular switch in the cell
Small Molecules and Ions as Second Messengers
Not all components of signal transduction pathways are proteins
Small, non-protein, water-soluble molecules or ions called second messengers are involved
Second messengers can spread throughout the cell by diffusion
Cyclic AMP and calcium ions (Ca2+) are the two most widely used second messengers
Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases
What If?
The question asks about the introduction of a molecule that inactivates phosphodiesterase into the cell
Page 13: Further regulation of cell metabolism
Other G protein systems inhibit adenylyl cyclase
Different signaling molecule activates a different receptor
Activates an inhibitory G protein that blocks activation of adenylyl cyclase
Cholera and the role of cAMP in G protein signaling pathways
Cholera is a disease caused by Vibrio cholerae bacteria
Acquired by drinking contaminated water
Bacteria form a biofilm on the lining of the small intestine and produce a toxin
Cholera toxin chemically modifies a G protein involved in regulating salt and water secretion
Modified G protein remains stuck in its active form, continuously stimulating adenylyl cyclase to make cAMP
High concentration of cAMP causes intestinal cells to secrete large amounts of salts into the intestines, leading to diarrhea and dehydration
Signaling pathways involving cyclic AMP or related messengers
Understanding of these pathways has led to treatments for certain conditions in humans
Cyclic GMP (cGMP) is produced in response to nitric oxide (NO) and acts as a second messenger
cGMP causes relaxation of muscles, such as those in the walls of arteries
Compound that inhibits the hydrolysis of cGMP to GMP is used as a treatment for chest pains and erectile dysfunction (Viagra)
Calcium Ions and Inositol Trisphosphate (IP3)
Signaling molecules in animals increase cytosolic concentration of calcium ions (Ca2+)
Calcium is widely used as a second messenger
Increasing cytosolic Ca2+ concentration causes various responses in animal cells
Hormonal and environmental stimuli can cause brief increases in cytosolic Ca2+ concentration in plant cells
Ca2+ is used as a second messenger in pathways triggered by G protein-coupled receptors and receptor tyrosine kinases
Ca2+ concentration in the cytosol is normally much lower than outside the cell
Calcium ions are actively transported out of the cell and imported into the endoplasmic reticulum
Small change in absolute numbers of ions represents a relatively large percentage change in calcium concentration
Signal transduction pathways can cause a rise in cytosolic calcium level by releasing Ca2+ from the cell's ER
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Cell communication involves signal transduction pathways
Second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG), are produced by cleavage of a certain kind of phospholipid in the plasma membrane
IP3 stimulates the release of calcium from the endoplasmic reticulum (ER)
Calcium can be considered a "third messenger"
Protein kinases play a role in signal transduction pathways
Phosphorylation cascade is involved in signal transduction pathways
Ligand binding to a receptor and activation of phospholipase C can affect calcium concentration in the cytosol
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Regulation of the cell's response in signal transduction pathways
Signaling pathways amplify the cell's response to a signal
Control points in the pathway contribute to the specificity of the response and coordination with other pathways
Scaffolding proteins enhance the overall efficiency of the response
Termination of the signal is crucial in regulating the response
Signal transduction pathways lead to regulation of transcription or cytoplasmic activities
Response can occur in the nucleus or cytoplasm
Transcription factors regulate gene expression
Signaling pathways can regulate the activity of proteins outside the nucleus
Malfunctioning of growth factor pathways can contribute to abnormal cell division and cancer development
The extent of the response is regulated, not simply turned "on" or "off"
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Amplification effect in cell signaling
Proteins persist in active form and process multiple molecules of substrate
Small number of epinephrine molecules can lead to release of glucose molecules from glycogen
Specificity of cell signaling and coordination of response
Different cells respond differently to the same signals
Response depends on collection of signal receptor proteins, relay proteins, and proteins needed for response
Different cells have different collections of proteins
Different pathways may have some molecules in common
Differences in other proteins account for differing responses
Receptor proteins and second messengers can regulate numerous proteins
Branching of pathways and cross-talk between pathways are important
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Signaling efficiency: scaffolding proteins and signaling complexes
Signaling pathways are simplified in illustrations
Most relay molecules are proteins and are too large to diffuse quickly
Scaffolding proteins increase efficiency of signal transduction
Scaffolding proteins hold together networks of signaling pathway proteins
Enhances speed and accuracy of signal transfer between cells
Scaffolding proteins may directly activate relay proteins
Importance of relay proteins in signaling pathways
Problems arise when these proteins are defective or missing
Example: Wiskott-Aldrich syndrome (WAS)
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Absence of a relay protein called WAS protein leads to abnormal bleeding, eczema, predisposition to infections, and leukemia.
Symptoms arise from the absence of the protein in cells of the immune system.
WAS protein is located beneath the immune cell surface and interacts with microfilaments of the cytoskeleton and signaling pathways.
The WAS protein is a branch point and an important intersection point in a complex signal transduction network that controls immune cell behavior.
When the WAS protein is absent, the cytoskeleton is not properly organized and signaling pathways are disrupted, leading to the symptoms.
Termination of the Signal
Inactivation mechanisms are essential in any cell-signaling pathway.
Molecular changes in signaling pathways must last only a short time for a cell to remain capable of responding to incoming signals.
Reversibility of changes produced by prior signals is necessary for a cell to receive new signals.
Binding of signaling molecules to receptors is reversible.
Cellular response occurs only when the concentration of receptors with bound signaling molecules is above a certain threshold.
Relay molecules return to their inactive forms through various means such as GTPase activity, phosphodiesterase, and protein phosphatases.
The cell is soon ready to respond to a fresh signal.
Concept Check 11.4
How can a target cell's response to a single hormone molecule result in a response that affects a million other molecules?
What if two cells have different scaffolding proteins, explain how they might behave differently in response to the same signaling molecule.
What if some human diseases are associated with malfunctioning protein phosphatases, how would such proteins affect signaling pathways?
Concept 11.5: Apoptosis integrates multiple cell-signaling pathways
Signaling pathway components interact with each other in various ways.
Cellular proteins often integrate multiple signals for the appropriate response.
Cellular suicide, known as apoptosis, is a controlled cell suicide process.
Infected, damaged, or cells at the end of their functional life span undergo apoptosis.
Apoptosis involves cellular agents chopping up and shedding membrane-bounded cell fragments.
Figure 11.19: Apoptosis of a human white blood cell
Apoptotic cell is shrinking and forming lobes ("blebs") which are shed as membrane-bounded cell fragments.
Next section: Mechanism of Hormone Action: Second messenger cAMP
Signaling initiation and termination in a single pathway can be complex.
Pathways have the potential to intersect with each other.
The next section will explore an important network of interacting pathways in the cell.
Page 19: Apoptosis and its Pathways
Apoptosis is a process of programmed cell death.
The pathway used for apoptosis depends on the type of cell and the signal that initiates it.
One major pathway involves certain mitochondrial proteins that form molecular pores in the mitochondrial outer membrane.
This causes the membrane to leak and release other proteins that promote apoptosis, including cytochrome c.
During apoptosis, the DNA and organelles of the cell are fragmented, and the cell shrinks and becomes lobed.
The cell's parts are packaged in vesicles and digested by specialized scavenger cells.
Apoptosis protects neighboring cells from damage.
The signal that triggers apoptosis can come from outside or inside the cell.
Outside the cell, signaling molecules from other cells can initiate a signal transduction pathway.
Within a cell with irretrievably damaged DNA, protein-protein interactions can pass along a signal for cell death.
Apoptosis in the Soil Worm Caenorhabditis elegans
The molecular mechanisms of apoptosis were studied in the soil worm Caenorhabditis elegans.
Researchers were able to work out the entire ancestry of each cell in C. elegans.
Apoptosis occurs exactly 131 times during normal development of C. elegans.
Apoptosis in C. elegans is triggered by signals that activate a cascade of "suicide" proteins in the cells destined to die.
Two key apoptosis genes in C. elegans are ced-3 and ced-4, which encode proteins essential for apoptosis.
Ced-9, a protein in the outer mitochondrial membrane, serves as a master regulator of apoptosis in C. elegans.
Ced-9 acts as a brake in the absence of a signal promoting apoptosis.
When a death signal is received, Ced-9 is inactivated, disabling the brake and activating the apoptotic pathway.
Proteases and nucleases are activated, leading to the fragmentation of proteins and DNA in the cell.
Apoptotic Pathways and the Signals That Trigger Them
In humans and other mammals, several different pathways involving caspases can carry out apoptosis.
About 15 different caspases are involved in these pathways.
The main proteases of apoptosis are called caspases.
In C. elegans, the chief caspase is the Ced-3 protein.
The molecular basis of apoptosis in C. elegans involves three critical proteins: Ced-3, Ced-4, and Ced-9.
Ced-9 inhibits Ced-4 activity when it is active.
When a death signal is received, Ced-9 is inactivated, relieving its inhibition of Ced-4.
Active Ced-4 activates Ced-3, a protease, which triggers a cascade of reactions leading to the activation of nucleases and other proteases.
This leads to the changes seen in apoptotic cells and eventually cell death.
Cell Communication and Apoptosis
Apoptosis in Development and Disease (Page 20)
Apoptosis is involved in the development of hands and feet in humans and paws in mammals.
Failure of apoptosis can result in webbed fingers and toes in humans.
Apoptosis is also implicated in degenerative diseases of the nervous system, such as Parkinson's and Alzheimer's disease.
In Alzheimer's disease, aggregated proteins activate an enzyme that triggers apoptosis, leading to loss of brain function.
Failure of cell suicide can result in cancer, such as human melanoma.
Faulty forms of the human version of the C. elegans Ced-4 protein have been linked to some cases of melanoma.
Signaling Pathways and Apoptosis
Signaling pathways feeding into apoptosis are elaborate due to the fundamental importance of the life-or-death question for cells.
General mechanisms of cell communication include ligand binding, protein-protein interactions, shape changes, cascades of interactions, and protein phosphorylation.
Concept Check 11.5
Example of apoptosis during embryonic development and its function in the developing embryo.
Protein defects that could cause apoptosis to occur when it should not and protein defects that could result in apoptosis not occurring when it should.
Apoptosis in Paw Development (Figure 11.21)
Apoptosis plays a role in the development of paws in mice and other mammals.
Interdigital tissue undergoes apoptosis, eliminating cells and forming digits.
Fluorescence light micrographs show the progression of apoptosis in embryonic mouse paws.
Key Gateways and Relay Proteins in Apoptosis
Relay proteins integrate signals from different sources and can initiate apoptosis.
Death-signaling ligands can activate caspases and other enzymes involved in apoptosis.
Alarm signals from inside the cell, such as DNA damage or protein misfolding, can also lead to apoptosis.
Cells integrate death signals and life signals from external and internal sources to make life-or-death decisions.
Evolution and Importance of Apoptosis
Apoptosis genes are conserved between nematodes and mammals, suggesting an early evolution of the mechanism.
Apoptosis is essential for the development and maintenance of all animals.
Apoptosis is crucial for the normal development of the nervous system in vertebrates.
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Signal transduction pathways involve molecular interactions that relay signals from receptors to target molecules in the cell.
Signal transduction pathways involve shape changes in proteins.
Phosphorylation cascades, involving protein kinases, activate proteins in the pathway.
Protein phosphatases remove phosphate groups, regulating protein activity.
Second messengers like cAMP and Ca2+ help broadcast signals quickly.
G proteins activate adenylyl cyclase to produce cAMP.
Tyrosine kinase pathways involve second messengers DAG and IP3.
IP3 can trigger an increase in Ca2+ levels.
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Cell signaling can lead to regulation of transcription or cytoplasmic activities.
Some pathways lead to a nuclear response, turning specific genes on or off.
Other pathways involve cytoplasmic regulation.
Cellular responses are regulated at multiple steps.
Proteins in a signaling pathway amplify the signal by activating multiple copies of the next component.
Scaffolding proteins increase signaling efficiency.
Pathway branching helps coordinate signals and responses.
Ligand binding is reversible, allowing for quick termination of signal response.
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Apoptosis is a type of programmed cell death.
Studies of Caenorhabditis elegans have clarified molecular details of apoptotic signaling pathways.
Death signals activate caspases and nucleases, enzymes involved in apoptosis.
Apoptotic signaling pathways exist in humans and other mammals.
Apoptosis can be triggered by signals from outside or inside the cell.
Summary of Key Concepts:
Signal transduction pathways are crucial for many processes.
Signaling mechanisms have an early evolutionary origin.
Bacterial cells can sense the local density of bacterial cells.
Local signaling involves direct contact or secretion of local regulators.
Long-distance signaling involves hormones and electrical signals.
Epinephrine triggers a three-stage cell-signaling pathway.
The response of a cell to a hormone is determined by specific factors.
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Reception is the binding of a signaling molecule to a receptor protein.
The binding between the ligand and receptor is highly specific.
Three major types of cell-surface transmembrane receptors:
G protein-coupled receptors (GPCRs) work with cytoplasmic G proteins.
Receptor tyrosine kinases (RTKs) form dimers and add phosphate groups to tyrosines.
Ligand-gated ion channels open or close in response to specific signaling molecules.
Abnormal GPCRs and RTKs are associated with human diseases.
Intracellular receptors are cytoplasmic or nuclear proteins that bind hydrophobic signaling molecules.
Vocabulary Self-Quiz:
Link provided for a self-quiz on the concepts discussed in the chapter.
Page 22: Cell Communication
Evolution Connection
Identify evolutionary mechanisms for cell-to-cell signaling systems in prokaryotes.
Scientific Inquiry
Epinephrine initiates a signal transduction pathway that leads to glycogen breakdown.
Caffeine blocks the activity of cAMP phosphodiesterase.
Propose a mechanism for how caffeine ingestion leads to heightened alertness and sleeplessness.
Science, Technology, and Society
Aging process is thought to be initiated at the cellular level.
Loss of cell's ability to respond to growth factors and signals after a certain number of cell divisions.
Research aims to understand aging and extend human lifespan.
Discuss the social and ecological consequences of greatly increased life expectancy.
Write About a Theme: Organization
Properties of life emerge at the biological level of the cell.
Apoptosis is a highly regulated process that is an emergent property.
Explain the role of apoptosis in animal development and functioning.
Describe how apoptosis is a process that emerges from the orderly integration of signaling pathways.
Synthesize Your Knowledge
There are five basic tastes: sour, salty, sweet, bitter, and umami.
Salt is detected when the concentration of salt outside a taste bud cell is higher than inside, causing a change in membrane potential.
Umami is a savory taste generated by glutamate.
Propose an explanation for why the taste of salt persists after eating flavored tortilla chips and rinsing the mouth.
Test Your Understanding
Level 1: Knowledge/Comprehension
Different types of receptors and their effects on membrane distribution.
Activation of receptor tyrosine kinases.
Lipid-soluble signaling molecules and target cells.
Identifying second messengers.
Apoptosis and its characteristics.
Level 2: Application/Analysis
Sutherland's observation of epinephrine's effect on liver cells.
Protein phosphorylation and its involvement in various processes.
Level 3: Synthesis/Evaluation
Drawing the apoptotic pathway