Cell Communication and Homeostasis

Cell Communication and Homeostasis
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Dynamic Homeostasis 2

What is (dynamic) homeostasis?
Homeostasis = The property of a system that regulates its internal environment to maintain stable, (relatively) constant conditions In living things, often terms “dynamic homeostasis” - what do you figure this indicates?

Feedback Control Homeostasis 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 occurs Consists of a sensor, a control center, and an effector pathway

Positive vs Negative Feedback loops may be positive or negative
Negative feedback mechanism: Maintains homeostasis by returning a changing condition back to its stable target point Discussion: although there are negative and positive operons, both types are a negative feedback mechanism - why?

Generalized Negative Feedback Model
hormone 1 gland lowers body condition high specific body condition low raises body condition gland hormone 2

Controlling Body Temperature
Nervous System Control Feedback Controlling Body Temperature nerve signals hypothalamus sweat dilates surface blood vessels high body temperature (37°C) low hypothalamus constricts surface blood vessels shiver nerve signals

Regulation of Blood Sugar
Endocrine System Control Feedback Regulation of Blood Sugar islets of Langerhans beta islet cells insulin body cells take up sugar from blood liver stores glycogen reduces appetite pancreas liver high blood sugar level (90mg/100ml) low liver releases glucose triggers hunger pancreas liver islets of Langerhans alpha islet cells glucagon

Positive vs Negative Alterations in negative feedback mechanisms -> deleterious consequences Discussion: People who are diabetic produce minimal insulin. What effect does this have on the blood sugar control feedback loop?

Positive vs Negative Positive 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

Generalized Positive Feedback Model
hormone 1 gland raises body condition high specific body condition Or… 11

Generalized Positive Feedback Model
hormone 1 gland lowers body condition low specific body condition 12

Discussion Describe a positive feedback loop in the case of asthma, taking into account variables such as: airway swelling/narrowing aiway irritation blood oxygen levels cortisol increasing heart & breathing rates lung oxygen content nervous system recognition of blood oxygen levels oxygen available to brain panic release of stress hormones such as cortisol

Maintaining Homeostasis
The activities and stability of cells, organisms, and also whole populations, communities, ecosystems etc. are affected by both biotic and abiotic factors Discussion: 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?

Cell Signaling 15

Cell Signaling Every 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 communication Cells do this by generating, transmitting, and receiving chemical signals

Cell Signaling Signals can be stimulatory… or inhibitory.

Cell Signaling Cell signaling (sometimes just called “signal transduction”) has three general stages: Reception Transduction Response

Cell Signaling - Reception
Signaling begins with the recognition of a chemical messenger by a receptor protein embedded in the cell membrane Chemical messenger = a ligand Different receptors “recognize” different ligands due to fit, in a one-to-one relationship (think enzymes!)

Cell Signaling - Reception
The ligand binding to the receptor changes the receptor’s conformation (shape), which initiates the next step, transduction

Cell 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

Signal Transduction The receptor protein was an integral protein that spanned the membrane When it changes conformation, the part of it exposed to the cytoplasm changes conformation too It does something new now in the cytoplasm, such as… Serving as an enzyme Opening 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.

Signal Transduction The 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!

Signal Transduction Signal transduction diagrams can follow some slightly different conventions, but common ones are: A stimulates B A inhibits B Translocation/Relocation B to C is a larger (amplified) response than A to B A B A B A A B C

Signal Transduction A and B subunits join to make C
A separates into subunits B and C Multistep pathway from A to B with some steps not shown A C B B A C A B

Discussion Consider 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?

Signal Transduction That example displayed a common signal transduction method: a phosphorylation cascade A series of protein kinases adding a phosphate group to the next protein in the sequence (protein kinase = acts like an enzyme activator using ATP) Reception Transduction Response mRNA NUCLEUS Gene P Active transcription factor Inactive DNA Phosphorylation cascade CYTOPLASM Receptor Growth factor

Phosphorylation Cascade

Cell Signaling Specificity
Which receptors and secondary messengers a cell possesses determines which signals it will respond to, and how This is why a liver and a heart cell will do two different things when activated by the same hormone, like epinephrin

Short-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.

Discussion QUICK! NO NOTES!
What do you remember about how neurons signal each other??

Cells have voltage! Opposite charges on opposite sides of cell membrane membrane is polarized negative inside; positive outside charge gradient stored 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). – – +

How does a nerve impulse travel?
Stimulus: nerve is stimulated reaches threshold potential open Na+ channels in cell membrane Na+ ions diffuse into cell charges reverse at that point on neuron positive inside; negative outside cell becomes depolarized – + Na+

Wave: nerve impulse travels down neuron change in charge opens next Na+ gates down the line “voltage-gated” channels Na+ ions continue to diffuse into cell “wave” moves down neuron = action potential Gate + – channel closed channel open – + Na+ action potential 

Re-set: 2nd wave travels down neuron K+ channels open K+ channels open up more slowly than Na+ channels K+ ions diffuse out of cell charges reverse back at that point negative inside; positive outside + – Na+ K+ action potential  Opening gates in succession = - same strength - same speed - same duration

Combined waves travel down neuron wave of opening ion channels moves down neuron signal moves in one direction      flow of K+ out of cell stops activation of Na+ channels in wrong direction + – Na+ action potential  K+

How does the wave jump the gap?
What happens at the end of the axon? Impulse has to jump the synapse! junction between neurons has to jump quickly from one cell to next How does the wave jump the gap? Synapse

from an electrical signal
Chemical synapse Events at synapse action potential depolarizes membrane opens Ca++ channels neurotransmitter vesicles fuse with membrane, release neurotransmitter to synapse  diffusion neurotransmitter binds with protein receptor Ligand-gated ion channels open neurotransmitter degraded or reabsorbed axon terminal action potential synaptic vesicles synapse Ca++ Calcium is a very important ion throughout your body. It will come up again and again involved in many processes. neurotransmitter acetylcholine (ACh) receptor protein muscle cell (fiber) We switched… from an electrical signal to a chemical signal

Nerve impulse in next neuron
K+ Post-synaptic neuron triggers nerve impulse in next nerve cell Neurotransmitter = ligand opens ligand-gated ion channels Na+ diffuses into cell K+ diffuses out of cell switch back to voltage-gated channel K+ Na+ ion channel binding site ACh Here we go again! – + Na+

Discussion How 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.”

Effects 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.

Long-Distance Signaling:
Endocrine System

Regulation Why are hormones needed?
chemical messages from one body part to another communication needed to coordinate whole body daily homeostasis & regulation of large scale changes solute levels in blood glucose, Ca++, salts, etc. metabolism growth development maturation reproduction growth hormones

Regulation & Communication
Animals rely on 2 systems for regulation endocrine system system of ductless glands secrete chemical signals directly into blood chemical travels to target tissue target cells have receptor proteins slow, long-lasting response nervous system system of neurons transmits “electrical” signal & release neurotransmitters to target tissue fast, short-lasting response Hormones 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.

Nervous & Endocrine systems linked
Hypothalamus = “master nerve control center” nervous system receives information from nerves around body about internal conditions releasing hormones: regulates release of hormones from pituitary Pituitary gland = “master gland” endocrine system secretes broad range of “tropic” hormones regulating other glands in body hypothalamus posterior pituitary anterior

How do hormones act on target cells
Lipid-based hormones hydrophobic & lipid-soluble diffuse across cell membrane & enter cells bind to receptor proteins in cytoplasm & nucleus bind to DNA as transcription factors turn on genes Protein-based hormones hydrophilic & not lipid soluble can’t diffuse across cell membrane bind to receptor proteins in cell membrane trigger secondary messenger pathway activate internal cellular response enzyme action, uptake or secretion of molecules…

Action of lipid (steroid) hormones
target cell blood S 1 S cross cell membrane protein carrier S 2 cytoplasm binds to receptor protein becomes transcription factor 5 mRNA read by ribosome 3 S plasma membrane 4 DNA mRNA 6 7 nucleus protein protein secreted ex: secreted protein = growth factor (hair, bone, muscle, gametes)

Action of protein hormones
signal-transduction pathway Action of protein hormones 1 signal protein hormone P plasma membrane binds to receptor protein activates G-protein activates enzyme cAMP receptor protein acts as 2° messenger transduction ATP GTP transduction: the action or process of converting something and especially energy or a message into another form activates cytoplasmic signal ATP activates enzyme 2 secondary messenger system cytoplasm activates enzyme 3 response target cell produces an action

Effects of stress on a body
Nerve signals Spinal cord (cross section) Hypothalamus Releasing hormone Nerve cell Anterior pituitary Blood vessel adrenal medulla secretes epinephrine & norepinephrine Nerve cell Adrenal cortex secretes mineralocorticoids & glucocorticoids ACTH Adrenal gland Kidney MEDULLA CORTEX (A) SHORT-TERM STRESS RESPONSE (B) LONG-TERM STRESS RESPONSE Effects of epinephrine and norepinephrine: 1. Glycogen broken down to glucose; increased blood glucose 2. Increased blood pressure 3. Increased breathing rate 4. Increased metabolic rate 5. Change in blood flow patterns, leading to increased alertness & decreased digestive & kidney activity Effects of mineralocorticoids: 1. Retention of sodium ions & water by kidneys 2. Increased blood volume & blood pressure Effects of glucocorticoids: 1. Proteins & fats broken down & converted to glucose, leading to increased blood glucose 2. Immune system suppressed

Ex: Action of epinephrine (adrenaline)
Ex: Action of epinephrine (adrenaline) signal adrenal gland 1 epinephrine activates G protein 3 activates adenylyl cyclase receptor protein in cell membrane GDP cAMP transduction 4 ATP 2 GTP activates protein kinase-A 5 activates GTP activates phosphorylase kinase cytoplasm released to blood activates glycogen phosphorylase 7 liver cell glycogen 6 glucose response

Benefits of a 2° messenger system
1 signal Activated adenylyl cyclase receptor protein 2 Not yet activated amplification 4 amplification 3 cAMP amplification 5 GTP G protein protein kinase 6 amplification Amplification! enzyme Cascade multiplier! 7 amplification FAST response! product

metamorphosis & maturation
Homology in hormones What does this tell you about these hormones? How could these hormones have different effects? prolactin growth hormone same gene family gene duplication? amphibians metamorphosis & maturation mammals milk production birds fat metabolism fish salt & water balance growth & development The 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!

Fighting the Enemy Within! Cell-to-Cell Signaling:
phagocytic leukocyte Fighting the Enemy Within! Cell-to-Cell Signaling: Immune System lymphocytes attacking cancer cell lymph system 54

What’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 outside lots of organisms want you for lunch! among other advantages, like shelter & reproduction, animals are a tasty nutrient- & vitamin-packed meal cells are packages of macromolecules animals must defend themselves against invaders (pathogens) viruses - HIV, flu, cold, measles, chicken pox bacteria - pneumonia, meningitis, tuberculosis Lyme disease Fungi - yeast (“Athlete’s foot”…) Protists - amoeba, malaria Attack from inside cancers = abnormal body cells Mmmmm, What’s in your lunchbox? 55

Immune System Immune defenses may be non-specific or specific
Non-specific = broad, defends against many kinds of attackers Specific = targets one kind or a small number of attackers Three lines of defense…

Lines of defense 1st line: Non-specific barriers
broad, external defense “walls & moats” skin & mucous membranes 2nd line: Non-specific patrols broad, internal defense “patrolling soldiers” leukocytes = phagocytic WBC 3rd line: True immune system specific, acquired immunity “elite trained units” lymphocytes & antibodies B cells & T cells 57

1st line: Non-specific External defense
Barrier skin Traps mucous membranes, cilia, hair, earwax Elimination coughing, sneezing, urination, diarrhea Unfavorable pH stomach acid, sweat, saliva, urine Lysozyme enzyme digests bacterial cell walls tears, sweat Lining of trachea: ciliated cells & mucus secreting cells 58

2nd line: Non-specific defenses
bacteria Patrolling cells & proteins attack many pathogens, but don’t “remember” for next time leukocytes phagocytic white blood cells macrophages, neutrophils, natural killer cells complement system proteins that destroy cells inflammation increase in body temp. increase capillary permeability attract macrophages fever macrophage yeast 59

Discussion What are the advantages of the non-specific defenses?
What are the disadvantages?

3rd line: Acquired (active) Immunity
Specific defense with memory lymphocytes B cells T cells antibodies immunoglobulins Responds to… antigens cellular name tags specific pathogens specific toxins abnormal body cells (cancer) B cell 61

How are invaders recognized?
Antigens Peripheral proteins - what does that mean? cellular “name tag” proteins “self” antigens no response from WBCs “foreign” antigens response from WBCs pathogens: viruses, bacteria, protozoa, parasitic worms, fungi, toxins non-pathogens: cancer cells, transplanted tissue, pollen “self” “foreign” 62

Specific Immune Response
Two “pathways” of response Cell-mediated immunity Call in specialist cells to target the pathogen! Humoral immunity Use antibodies! Cell-mediated and humoral pathways use a variety of white blood cells, or lymphocytes…

Lymphocytes B cells T cells Macrophages mature in bone marrow
humoral response system produce antibodies T cells mature in thymus cellular response system attack invaded cells Macrophages Generalist 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

Cell-Mediated Immunity
Step 1: A generalist macrophage engulfs an invader, including its antigens Step 2: The macrophage “presents” the invader’s antigens - basically, it pops them out of its own membrane! It becomes an antigen-presenting cell 65

How is any cell tagged with antigens?
Major histocompatibility (MHC) proteins proteins which constantly carry bits of cellular material from the cytosol to the cell surface “snapshot” of what is going on inside cell give the surface of cells a unique label or “fingerprint” MHC protein Who goes there? self or foreign? T or B cell MHC proteins displaying self-antigens 66

How do T cells know a cell is infected?
Infected cells digest some pathogens MHC proteins carry pieces to cell surface foreign antigens now on cell membrane called Antigen Presenting Cell (APC) macrophages can also serve as APC tested by Helper T cells MHC proteins displaying foreign antigens infected cell TH cell WANTED T cell with antigen receptors 67

Cell-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 antigen Mature and proliferate into helper T-cells and cytotoxic T-cells This is cell-to-cell signaling! 68

http://highered. mcgraw-hill
Helper T-Cells Signal cytotoxic T-cells and B-cells (humoral immunity pathway, up next) to seek out and target that antigen Some become “memory T-cells,” which hang out in the body, ready to immediately respond if that antigen ever returns! 69

Cytotoxic T-Cells Destroys infected body cells binds to target cell
secretes perforin protein punctures cell membrane of infected cell apoptosis vesicle Killer T cell Killer T cell binds to infected cell cell membrane perforin punctures cell membrane cell membrane infected cell destroyed target cell 70

Humoral Response Y Y Y Y Y Y Y Y Y Y
Antibodies = Proteins that bind to a specific antigen multi-chain proteins binding region matches molecular shape of antigens each antibody is unique & specific millions of antibodies respond to millions of foreign antigens tagging “handcuffs” “this is foreign…gotcha!” Y Y Y antigen- binding site on antibody antigen Y Y Y Y variable binding region Y Y each B cell has ~50,000 antibodies 71

What do antibodies do to invaders?
neutralize capture precipitate apoptosis macrophage eating tagged invaders invading pathogens tagged with antibodies Y 72

Humoral Response Step 1: If triggered by a helper T-cell, B cells, upon encountering the antigen, bind to the pathogen that bears it Step 2: The bound B-cell proliferates into two new kinds of B cells… 73

Humoral Respose Plasma B-Cells: Memory B-Cells:
Produce antibodies against that antigen for a few days Memory B-Cells: Long-lived, will rapidly proliferate into fresh plasma cells for an instant counter-offensive if the antigen is ever re-encountered 74

Humoral Response The first ever encounter with the pathogen = primary response (or primary immunity), moderately effective Re-encounter in the future = secondary response. Immediate, powerful, decisive! 76

Discussion Use 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

pathogen invasion antigen exposure antigens on infected cells
Immune response pathogen invasion antigen exposure skin skin free antigens in blood antigens on infected cells macrophages (APC) humoral response cellular response B cells alert helper T cells alert T cells plasma B cells memory B cells memory T cells cytotoxic T cells Y antibodies Y antibodies 78

Vaccinations Immune system exposed to harmless version of pathogen
stimulates B cell system to produce antibodies to pathogen rapid response on future exposure creates immunity without getting disease! Most successful against viruses 79

HIV & AIDS Human Immunodeficiency Virus
virus infects helper T cells AIDS: Acquired ImmunoDeficiency Syndrome AIDS 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

Cell Signaling: Wrap-Up
81

Evolution of Homeostasis & Signaling
Continuity of homeostatic mechanisms is a means of studying shared ancestry A 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 conditions Just like changes to a physical body structure!

Evolution of Homeostasis
For example, the control of blood osmolarity has been basically the same from flatworms through vertebrates Excretory demands haven’t changed much, so neither has the control mechanism:

osmoreceptors in hypothalamus
Endocrine System Control Feedback Blood Osmolarity increase thirst osmoreceptors in hypothalamus ADH increased water reabsorption nephron pituitary high nephron blood osmolarity blood pressure JuxtaGlomerular Apparatus low nephron (JGA) increased water & salt reabsorption adrenal gland renin aldosterone angiotensinogen angiotensin

Evolution 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…

Discussion What parts of fish, amphibian, and mammal control of blood oxygen are homologous? What are the differences?

Evolution of Homeostasis & Signaling
Correct and appropriate signaling mechanisms are under strong selective pressure A single simple change to a single protein in a signaling pathway can have a massive effect, for better or for worse!

Signaling in Prokaryotes
Signaling isn’t just for the multicellular! Prokaryotes signal to each other in quorum sensing Example: Signals passed between neighboring bacteria trigger the expression of genes for forming attachment surface proteins And the more bacteria you’re surrounded by, the more and more of that signal you’re getting Discussion: What’s advantageous about that?

Cell Communication and Homeostasis

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