3What is (dynamic) homeostasis? Homeostasis = The property of a system that regulates its internal environment to maintain stable, (relatively) constant conditionsIn living things, often terms “dynamic homeostasis” - what do you figure this indicates?
4Feedback ControlHomeostasis is often maintained through the use of feedback systems (or loops).A feedback system uses the consequences of the process (too much or too little produced) to regulate the rate at which the process occursConsists of a sensor, a control center, and an effector pathway
5Positive vs Negative Feedback loops may be positive or negative Negative feedback mechanism: Maintains homeostasis by returning a changing condition back to its stable target pointDiscussion: although there are negative and positive operons, both types are a negative feedback mechanism - why?
6Generalized Negative Feedback Model hormone 1glandlowers body conditionhighspecific body conditionlowraises body conditionglandhormone 2
7Controlling Body Temperature Nervous System ControlFeedbackControlling Body Temperaturenerve signalshypothalamussweatdilates surface blood vesselshighbody temperature(37°C)lowhypothalamusconstricts surface blood vesselsshivernerve signals
8Regulation of Blood Sugar Endocrine System ControlFeedbackRegulation of Blood Sugarislets of Langerhans beta islet cellsinsulinbody cells take up sugar from bloodliver stores glycogenreduces appetitepancreasliverhighblood sugar level(90mg/100ml)lowliver releases glucosetriggers hungerpancreasliverislets of Langerhans alpha islet cellsglucagon
9Positive vs NegativeAlterations in negative feedback mechanisms -> deleterious consequencesDiscussion: People who are diabetic produce minimal insulin. What effect does this have on the blood sugar control feedback loop?
10Positive vs NegativePositive feedback mechanism: Does not maintain homeostasis; instead, amplifies responses and processes, moving the system further and further away from starting conditions.Example: labor in childbirth
11Generalized Positive Feedback Model hormone 1glandraises body conditionhighspecific body conditionOr…11
12Generalized Positive Feedback Model hormone 1glandlowers body conditionlowspecific body condition12
13DiscussionDescribe a positive feedback loop in the case of asthma, taking into account variables such as:airway swelling/narrowingaiway irritationblood oxygen levelscortisol increasing heart & breathing rateslung oxygen contentnervous system recognition of blood oxygen levelsoxygen available to brainpanicrelease of stress hormones such as cortisol
14Maintaining Homeostasis The activities and stability of cells, organisms, and also whole populations, communities, ecosystems etc. are affected by both biotic and abiotic factorsDiscussion: Think back through the course! Can you come up with a biotic and abiotic factor that affects cell activities? Organism? Population or community?AND, how does the cell/organism/population maintain homeostasis when that biotic or abiotic variable changes?
16Cell SignalingEvery feedback loop in an organism that we discussed, positive or negative, has one thing in common: cell signaling.In a multicellular (and even unicellular!) organism, recognizing and responding to changes, internal or external, necessitates cell-to-cell communicationCells do this by generating, transmitting, and receiving chemical signals
17Cell SignalingSignals can bestimulatory…or inhibitory.
18Cell SignalingCell signaling (sometimes just called “signal transduction”) has three general stages:ReceptionTransductionResponse
19Cell Signaling - Reception Signaling begins with the recognition of a chemical messenger by a receptor protein embedded in the cell membraneChemical messenger = a ligandDifferent receptors “recognize” different ligands due to fit, in a one-to-one relationship (think enzymes!)
20Cell Signaling - Reception The ligand binding to the receptor changes the receptor’s conformation (shape), which initiates the next step, transduction
21Cell Signaling - Transduction Signal transduction is the process by which a signal is converted to a cellular response.The utility of signal transduction is signal amplification: through a cascade of chemical reactions, a single recognized ligand will be able to trigger a proportionally larger response
22Signal TransductionThe receptor protein was an integral protein that spanned the membraneWhen it changes conformation, the part of it exposed to the cytoplasm changes conformation tooIt does something new now in the cytoplasm, such as…Serving as an enzymeOpening up a channel between cell interior and exterior (like ion channels in neurons!)Release a polypeptide from itself into the cytoplasm…which is the first in what will be a series of chemical reactions, using a variety of second messengers inside the cell.
23Signal TransductionThe end result of the signal cascade could be producing or destroying transcription factors, activating enzymes, cytoskeleton rearrangement… and often many related results from the same signal!
24Signal TransductionSignal transduction diagrams can follow some slightly different conventions, but common ones are:A stimulates BA inhibits BTranslocation/RelocationB to C is a larger (amplified) response than A to BABABAABC
25Signal Transduction A and B subunits join to make C A separates into subunits B and CMultistep pathway from A to B with some steps not shownACBBACAB
26DiscussionConsider this very simple diagram of a signal cascade (bigger image on next slide), and answer:What’s happening? What is the ligand? What are the second messengers? Does EGF trigger or inhibit gene regulation?
28Signal TransductionThat example displayed a common signal transduction method: a phosphorylation cascadeA series of protein kinases adding a phosphate group to the next protein in the sequence (protein kinase = acts like an enzyme activator using ATP)ReceptionTransductionResponsemRNANUCLEUSGenePActivetranscriptionfactorInactiveDNAPhosphorylationcascadeCYTOPLASMReceptorGrowth factor
30Cell Signaling Specificity Which receptors and secondary messengers a cell possesses determines which signals it will respond to, and howThis is why a liver and a heart cell will do two different things when activated by the same hormone, like epinephrin
31Short-Distance Signaling: Nervous System Every time you move a muscle & every time you think a thought, your nerve cells are hard at work. They are processing information: receiving signals, deciding what to do with them, & dispatching new messages off to their neighbors. Some nerve cells communicate directly with muscle cells, sending them the signal to contract. Other nerve cells are involved solely in the bureaucracy of information, spending their lives communicating only with other nerve cells. But unlike our human bureaucracies, this processing of information must be fast in order to keep up with the ever-changing demands of life.
32Discussion QUICK! NO NOTES! What do you remember about how neurons signal each other??
33Cells have voltage!Opposite charges on opposite sides of cell membranemembrane is polarizednegative inside; positive outsidecharge gradientstored energy (like a battery)+This is an imbalanced condition.The positively + charged ions repel each other as do the negatively - charged ions. They “want” to flow down their electrical gradient and mix together evenly.This means that there is energy stored here, like a dammed up river.Voltage is a measurement of stored electrical energy. Like “Danger High Voltage” = lots of energy (lethal).––+
34How does a nerve impulse travel? Stimulus: nerve is stimulatedreaches threshold potentialopen Na+ channels in cell membraneNa+ ions diffuse into cellcharges reverse at that point on neuronpositive inside; negative outsidecell becomes depolarized–+Na+
35How does a nerve impulse travel? Wave: nerve impulse travels down neuronchange in charge opens next Na+ gates down the line“voltage-gated” channelsNa+ ions continue to diffuse into cell“wave” moves down neuron = action potentialGate+–channel closedchannel open–+Na+action potential
36How does a nerve impulse travel? Re-set: 2nd wave travels down neuronK+ channels openK+ channels open up more slowly than Na+ channelsK+ ions diffuse out of cellcharges reverse back at that pointnegative inside; positive outside+–Na+K+action potential Opening gates in succession =- same strength- same speed- same duration
37How does a nerve impulse travel? Combined waves travel down neuronwave of opening ion channels moves down neuronsignal moves in one direction flow of K+ out of cell stops activation of Na+ channels in wrong direction+–Na+action potential K+
38How does the wave jump the gap? What happens at the end of the axon?Impulse has to jump the synapse!junction between neuronshas to jump quickly from one cell to nextHow does the wave jump the gap?Synapse
39from an electrical signal Chemical synapseEvents at synapseaction potential depolarizes membraneopens Ca++ channelsneurotransmitter vesicles fuse with membrane, release neurotransmitter to synapse diffusionneurotransmitter binds with protein receptorLigand-gated ion channels openneurotransmitter degraded or reabsorbedaxon terminalaction potentialsynaptic vesiclessynapseCa++Calcium is a very important ion throughout your body. It will come up again and again involved in many processes.neurotransmitter acetylcholine (ACh)receptor proteinmuscle cell (fiber)We switched…from an electrical signalto a chemical signal
40Nerve impulse in next neuron K+Post-synaptic neurontriggers nerve impulse in next nerve cellNeurotransmitter = ligandopens ligand-gated ion channelsNa+ diffuses into cellK+ diffuses out of cellswitch back to voltage-gated channelK+Na+ion channelbinding siteAChHere we go again!–+Na+
41DiscussionHow do neurons illustrate the basic principles of signal transduction pathways?“Signaling begins with the recognition of a chemical messenger, a ligand, by a receptor protein. Different receptors recognize different ligands, which can be peptides, small chemicals, or proteins, in a one-to-one relationship. A receptor protein recognizes signal molecules, causing the receptor protein’s shape to change, which initiates transduction of the signal. Second messengers (hint: ions in this case) are often essential to the function of the cascade.”
42Effects of Changes in Pathways Neurons illustrate what can happen when a signaling pathway is tampered with!SSRIs like Prozac and Zoloft block the channels that permit the presynaptic neuron to take the neurotransmitter serotonin back in.Serotonin is used by neurons in the “happiness” pathways in the brain. What’s the effect? Discuss using the terminology of cell signaling.
44Regulation Why are hormones needed? chemical messages from one body part to anothercommunication needed to coordinate whole bodydaily homeostasis & regulation of large scale changessolute levels in bloodglucose, Ca++, salts, etc.metabolismgrowthdevelopmentmaturationreproductiongrowth hormones
45Regulation & Communication Animals rely on 2 systems for regulationendocrine systemsystem of ductless glandssecrete chemical signals directly into bloodchemical travels to target tissuetarget cells have receptor proteinsslow, long-lasting responsenervous systemsystem of neuronstransmits “electrical” signal & release neurotransmitters to target tissuefast, short-lasting responseHormones coordinate slower but longer–acting responses to stimuli such as stress, dehydration, and low blood glucose levels. Hormones also regulate long–term developmental processes by informing different parts of the body how fast to grow or when to develop the characteristics that distinguish male from female or juvenile from adult. Hormone–secreting organs, called endocrine glands, are referred to as ductless glands because they secrete their chemical messengers directly into extracellular fluid. From there, the chemicals diffuse into the circulation.
46Nervous & Endocrine systems linked Hypothalamus = “master nerve control center”nervous systemreceives information from nerves around body about internal conditionsreleasing hormones: regulates release of hormones from pituitaryPituitary gland = “master gland”endocrine systemsecretes broad range of “tropic” hormones regulating other glands in bodyhypothalamusposteriorpituitaryanterior
47How do hormones act on target cells Lipid-based hormoneshydrophobic & lipid-solublediffuse across cell membrane & enter cellsbind to receptor proteins in cytoplasm & nucleusbind to DNA as transcription factorsturn on genesProtein-based hormoneshydrophilic & not lipid solublecan’t diffuse across cell membranebind to receptor proteins in cell membranetrigger secondary messenger pathwayactivate internal cellular responseenzyme action, uptake or secretion of molecules…
48Action of lipid (steroid) hormones target cellbloodS1Scross cell membraneproteincarrierS2cytoplasmbinds to receptor proteinbecomes transcription factor5mRNA read by ribosome3Splasma membrane4DNAmRNA67nucleusproteinprotein secretedex: secreted protein = growth factor (hair, bone, muscle, gametes)
49Action of protein hormones signal-transduction pathwayAction of protein hormones1signalprotein hormonePplasma membranebinds to receptor proteinactivatesG-proteinactivates enzymecAMPreceptor proteinacts as 2° messengertransductionATPGTPtransduction: the action or process of converting something and especially energy or a message into another formactivates cytoplasmic signalATPactivatesenzyme2secondarymessenger systemcytoplasmactivatesenzyme3responsetarget cellproduces an action
50Effects of stress on a body NervesignalsSpinal cord(cross section)HypothalamusReleasinghormoneNervecellAnterior pituitaryBlood vesseladrenal medullasecretes epinephrine& norepinephrineNerve cellAdrenal cortexsecretesmineralocorticoids& glucocorticoidsACTHAdrenalglandKidneyMEDULLACORTEX(A) SHORT-TERM STRESS RESPONSE(B) LONG-TERM STRESS RESPONSEEffects of epinephrine and norepinephrine:1. Glycogen broken down to glucose; increased blood glucose2. Increased blood pressure3. Increased breathing rate4. Increased metabolic rate5. Change in blood flow patterns, leading to increased alertness & decreased digestive & kidney activityEffects ofmineralocorticoids:1. Retention of sodium ions & water by kidneys2. Increased blood volume & blood pressureEffects ofglucocorticoids:1. Proteins & fats broken down & converted to glucose, leading to increased blood glucose2. Immune system suppressed
51Ex: Action of epinephrine (adrenaline) Ex: Action of epinephrine (adrenaline)signaladrenal gland1epinephrineactivates G protein3activates adenylyl cyclasereceptorproteinin cell membraneGDPcAMPtransduction4ATP2GTPactivatesprotein kinase-A5activates GTPactivatesphosphorylase kinasecytoplasmreleased to bloodactivatesglycogen phosphorylase7liver cellglycogen6glucoseresponse
52Benefits of a 2° messenger system 1signalActivated adenylyl cyclasereceptor protein2Not yetactivatedamplification4amplification3cAMPamplification5GTPG proteinprotein kinase6amplificationAmplification!enzymeCascade multiplier!7amplificationFAST response!product
53metamorphosis & maturation Homology in hormonesWhat does this tell you about these hormones?How could these hormones have different effects?prolactingrowth hormonesame gene familygene duplication?amphibiansmetamorphosis & maturationmammalsmilk productionbirdsfat metabolismfishsalt & water balancegrowth & developmentThe most remarkable characteristic of prolactin (PRL) is the great diversity of effects it produces in different vertebrate species. For example, prolactin stimulates mammary gland growth and milk synthesis in mammals; regulates fat metabolism and reproduction in birds; delays metamorphosis in amphibians, where it may also function as a larval growth hormone; and regulates salt and water balance in freshwater fishes. This list suggests that prolactin is an ancient hormone whose functions have diversified during the evolution of the various vertebrate groups.Growth hormone (GH) is so similar structurally to prolactin that scientists hypothesize that the genes directing their production evolved from the same ancestral gene. Gene duplication!
54Fighting the Enemy Within! Cell-to-Cell Signaling: phagocytic leukocyteFighting the Enemy Within!Cell-to-Cell Signaling:Immune Systemlymphocytesattackingcancer celllymphsystem54
55What’s in your lunchbox? Why an immune system?Chemical defense against infections that disrupt dynamic homeostasis! (Animals aren’t the only organisms with defenses but we’re focusing on us)Attack from outsidelots of organisms want you for lunch!among other advantages, like shelter & reproduction, animals are a tasty nutrient- & vitamin-packed mealcells are packages of macromoleculesanimals must defend themselves against invaders (pathogens)viruses - HIV, flu, cold, measles, chicken poxbacteria - pneumonia, meningitis, tuberculosis Lyme diseaseFungi - yeast (“Athlete’s foot”…)Protists - amoeba, malariaAttack from insidecancers = abnormal body cellsMmmmm,What’s in your lunchbox?55
56Immune System Immune defenses may be non-specific or specific Non-specific = broad, defends against many kinds of attackersSpecific = targets one kind or a small number of attackersThree lines of defense…
592nd line: Non-specific defenses bacteriaPatrolling cells & proteinsattack many pathogens, but don’t “remember” for next timeleukocytesphagocytic white blood cellsmacrophages, neutrophils, natural killer cellscomplement systemproteins that destroy cellsinflammationincrease in body temp.increase capillary permeabilityattract macrophagesfevermacrophageyeast59
60Discussion What are the advantages of the non-specific defenses? What are the disadvantages?
613rd line: Acquired (active) Immunity Specific defense with memorylymphocytesB cellsT cellsantibodiesimmunoglobulinsResponds to…antigenscellular name tagsspecific pathogensspecific toxinsabnormal body cells (cancer)B cell61
62How are invaders recognized? AntigensPeripheral proteins - what does that mean?cellular “name tag” proteins“self” antigensno response from WBCs“foreign” antigensresponse from WBCspathogens: viruses, bacteria, protozoa, parasitic worms, fungi, toxinsnon-pathogens: cancer cells, transplanted tissue, pollen“self”“foreign”62
63Specific Immune Response Two “pathways” of responseCell-mediated immunityCall in specialist cells to target the pathogen!Humoral immunityUse antibodies!Cell-mediated and humoral pathways use a variety of white blood cells, or lymphocytes…
64Lymphocytes B cells T cells Macrophages mature in bone marrow humoral response systemproduce antibodiesT cellsmature in thymuscellular response systemattack invaded cellsMacrophagesGeneralist cells from the 2nd line of defense that can also interact with B and T cells in this 3rd line of defense, as you’ll see!Tens of millions of different T cells are produced, each one specializing in the recognition of oen particar antigen.64
65Cell-Mediated Immunity Step 1: A generalist macrophage engulfs an invader, including its antigensStep 2: The macrophage “presents” the invader’s antigens - basically, it pops them out of its own membrane!It becomes an antigen-presenting cell65
66How is any cell tagged with antigens? Major histocompatibility (MHC) proteinsproteins which constantly carry bits of cellular material from the cytosol to the cell surface“snapshot” of what is going on inside cellgive the surface of cells a unique label or “fingerprint”MHC proteinWho goes there?self or foreign?T or B cellMHC proteinsdisplaying self-antigens66
67How do T cells know a cell is infected? Infected cells digest some pathogensMHC proteins carry pieces to cell surfaceforeign antigens now on cell membranecalled Antigen Presenting Cell (APC)macrophages can also serve as APCtested by Helper T cellsMHC proteins displaying foreign antigensinfected cellTH cellWANTEDT cell with antigen receptors67
68Cell-Mediated Immunity Step 3: An immature T-cell binds to the antigen-presenting cell; the presented antigens signal the T-cell, trigger it to:Release recruitment signals that, through signal transduction, cause other immune cells to seek out and target that same antigenMature and proliferate into helper T-cells and cytotoxic T-cellsThis is cell-to-cell signaling!68
69http://highered. mcgraw-hill Helper T-CellsSignal cytotoxic T-cells and B-cells (humoral immunity pathway, up next) to seek out and target that antigenSome become “memory T-cells,” which hang out in the body, ready to immediately respond if that antigen ever returns!69
70Cytotoxic T-Cells Destroys infected body cells binds to target cell secretes perforin proteinpunctures cell membrane of infected cellapoptosisvesicleKiller T cellKiller T cell binds to infected cellcell membraneperforin punctures cell membranecell membraneinfected celldestroyedtarget cell70
71Humoral Response Y Y Y Y Y Y Y Y Y Y Antibodies = Proteins that bind to a specific antigenmulti-chain proteinsbinding region matches molecular shape of antigenseach antibody is unique & specificmillions of antibodies respond to millions of foreign antigenstagging “handcuffs”“this is foreign…gotcha!”YYYantigen- binding site on antibodyantigenYYYYvariable binding regionYYeach B cell has ~50,000 antibodies71
72What do antibodies do to invaders? neutralizecaptureprecipitateapoptosismacrophage eating tagged invadersinvading pathogens tagged with antibodiesY72
73Humoral ResponseStep 1: If triggered by a helper T-cell, B cells, upon encountering the antigen, bind to the pathogen that bears itStep 2: The bound B-cell proliferates into two new kinds of B cells…73
74Humoral Respose Plasma B-Cells: Memory B-Cells: Produce antibodies against that antigen for a few daysMemory B-Cells:Long-lived, will rapidly proliferate into fresh plasma cells for an instant counter-offensive if the antigen is ever re-encountered74
76Humoral ResponseThe first ever encounter with the pathogen = primary response (or primary immunity), moderately effectiveRe-encounter in the future = secondary response.Immediate, powerful, decisive!76
77DiscussionUse the conventions of cell signaling diagrams that we learned to construct a flowchart of specific immunity events! Include both humoral and cell-mediated immunity in the same diagram.Figure 12.19
78pathogen invasion antigen exposure antigens on infected cells Immune responsepathogen invasion antigen exposureskinskinfree antigens in bloodantigens on infected cellsmacrophages(APC)humoral responsecellular responseB cellsalerthelper T cellsalertT cellsplasma B cellsmemory B cellsmemory T cellscytotoxic T cellsYantibodiesYantibodies78
79Vaccinations Immune system exposed to harmless version of pathogen stimulates B cell system to produce antibodies to pathogenrapid response on future exposurecreates immunity without getting disease!Most successful against viruses79
80HIV & AIDS Human Immunodeficiency Virus virus infects helper T cellsAIDS: Acquired ImmunoDeficiency SyndromeAIDS itself doesn’t kill HIV-positive patients.Discussion: If AIDS doesn’t kill HIV-positive patients, what does? What is the specific effect of infected T-cells? How does this alter cell-mediated immunity? Humoral immunity?80
82Evolution of Homeostasis & Signaling Continuity of homeostatic mechanisms is a means of studying shared ancestryA homeostatic mechanism can be thought of as a “structure,” like an organ or a limb - it can show homology, analogy, vestigiality…Changes to homeostatic mechanisms may occur in response to changes in environmental conditionsJust like changes to a physical body structure!
83Evolution of Homeostasis For example, the control of blood osmolarity has been basically the same from flatworms through vertebratesExcretory demands haven’t changed much, so neither has the control mechanism:
84osmoreceptors in hypothalamus Endocrine System ControlFeedbackBlood Osmolarityincrease thirstosmoreceptors in hypothalamusADHincreased water reabsorptionnephronpituitaryhighnephronblood osmolarityblood pressureJuxtaGlomerular Apparatuslownephron(JGA)increased water & salt reabsorptionadrenal glandreninaldosteroneangiotensinogenangiotensin
85Evolution of Homeostasis On the other hand, when environmental demands change, so does the homeostatic mechanism that responds to them!Consider control of blood oxygen.Water is liquid, low oxygen. Air is non-liquid (and drying), high oxygen.So…
86DiscussionWhat parts of fish, amphibian, and mammal control of blood oxygen are homologous? What are the differences?
87Evolution of Homeostasis & Signaling Correct and appropriate signaling mechanisms are under strong selective pressureA single simple change to a single protein in a signaling pathway can have a massive effect, for better or for worse!
88Signaling in Prokaryotes Signaling isn’t just for the multicellular!Prokaryotes signal to each other in quorum sensingExample: Signals passed between neighboring bacteria trigger the expression of genes for forming attachment surface proteinsAnd the more bacteria you’re surrounded by, the more and more of that signal you’re gettingDiscussion: What’s advantageous about that?