Midterm #2 Flashcards
1
Q
MHC 1: what they bind
MHC 2: what they bind
A
- MHC 1: bind peptides derived from proteins made in the cell itself
- MHC 2: bind and display peptides from protein that has been phagocytized
2
Q
Purpose of MHC Molecules
A
- allow certain cells of the immune system to examine them via T cell receptors
3
Q
MHC 1: Structure
A
- two polypeptide chains
- first is long and consists of an intracellular domain, a transmembrane domain, and three extracellular domains
- second polypeptide chain is short and consists of one domain
4
Q
What should you notice?
A
Notice:
- peptide nestled in the top of the molecule
- in this context that the TCR receptor binds its specific peptide antigen
- Domains based on beta sheets
- homologous with the domains from which antibodies and T cell receptors are built
- alpha helices that create the groove in which the peptide is bound
5
Q
Steps from protein in cell to being expressed in MHC I molecule on the surface of the cell.
A
- Marked for destruction by ubiquitin
-
Ubiquitin ligases have the inherent ability to recognize abnormal proteins
- Virally infected/misfolded protein
-
Ubiquitin ligases have the inherent ability to recognize abnormal proteins
- Protein degraded to peptides by proteosome
- typically 9 amino acids
- peptides are transferred into the rough ER via a TAP transporter
- Meanwhile, an MHC I molecule is synthesized and placed in the membrane of the rough ER
- peptide binds in the groove in an MHC I molecule
- combination moves through the Golgi apparatus and into a secretion vesicle
- Exocytosis of the secretion vesicle places the MHC I molecule with its peptide on the surface of the cell
- peptide and MHC I molecule are now in position to be recognized by a T cell receptor on a T cell
6
Q
MHC II: Structure
A
- also has two polypeptide chains
- each polypeptide chain consists of an intracellular domain, a transmembrane domain, and two extracellular domains
- domain structure is similar to the MHC I molecule.
- big difference, however, is that a peptide from a phagocytized protein is bound the the MHC II molecule on the surface of the cell
7
Q
Steps in phagocystosed protein being expressed on MHC II molecule
A
- pathogen is phagocytized, winding up in a phagocytic vesicle
- lysosome with proteases fuses with the phagocytic vesicle, and the proteases digest the proteins into peptides
- Meanwhile the MHC II molecule is synthesized in the rough ER
- vesicle with the MHC II molecule now fuses with the vesicle containing the peptides, and a peptide bind to each MHC II molecule
- Exocytosis again places the MHC molecule and its peptide on the surface of the cell
- peptide and MHC II molecule are now in position to be recognized by a T cell receptor on a T cell
8
Q
Do you remember the term for the general type of molecule used by phagocytes to recognize a newly encountered foreign molecule? In other words, what is the general type of molecule used to recognize an antigen before a specific immune response has had a chance to make antibodies or T cell receptors?
A
A good term is innate receptors. One important group is the toll-like receptors. Another is the mannose receptor, which recognizes a repeating carbohydrate pattern
9
Q
Do you recall the term for the type of molecule that specifically binds the peptide displayed on an MHC molecule?
A
T cell receptor
10
Q
Dendritic Cells: Role and Action
A
- distributed throughout the body
- phagocytosis is their key process
- not primarily for the purpose of destroying microbes
- capture antigens and transport them to lymphoid tissue
- facilitate the development of an immune response
- Display peptides in MHC II molecule
11
Q
Helper T-Cell: Role and Action with dendritic cells
A
- In lymphoid tissue
- check to see if their T cell receptors specifically bind the peptide displayed in the MHC II molecule on dendritic cell
- certain dendritic cells also have a mechanism for displaying peptides on MHC I molecules
12
Q
Two Common Features of T-Cells
A
- All T cells have T cell receptors
- remain attached to the membranes of the T cells
- always recognize peptide antigens presented on MHC molecules
*
13
Q
CD4+ T-Cells
A
- bind peptides displayed on MHC II molecules
- Only with phagocytic cells
- dendritic cells (or macrophages)
- B cells
14
Q
Activated T-Cells
A
- T-Helper Cells
- T cell recognizes its specific peptide antigen presented on a dendritic cell or B cell
15
Q
TH1 vs. TH2 Cells: Tendency to Form
A
TH1 tend to form when:
- lots of strong stimulation by the phagocytized antigen
- lots of activation of the innate immune system
TH2 tend to form when:
- weaker, more prolonged stimulation
- less activation of innate mechanisms
16
Q
Important Role of TH1
A
- travel around the body to macrophages that have phagocytized the antigen
- bind and release IFN-gamma
- increases the fusion of lysosomes with phagosomes
17
Q
Why aren’t macrophages always active?
A
- Killing mechanisms can damage the body as well
18
Q
Which of the following do you suppose is treated sometimes with IFN-gamma?
a. hepatitis A
b. hepatitis B
c. multiple sclerosis
d. chronic granulomatous disease
e. rheumatoid arthritis
A
D: You have got it! The interferon-gamma would be expected to stimulate exactly the process that is weak in macrophages in this disorder.
19
Q
Helper T Cells and “helping B cells”
A
- Help B cell’s respond to antigens
- Many antigens cannot by themselves cause a specific B cell to divide into a clone of antibody secreting plasma cells
- B Cell Divide into Clone:
- Phagocytose antigen and display peptides on MHC II
- activated helper T must bind to the cell
- T helper release appropriate cytokines
20
Q
TH1 vs TH2: Types of antibodies made
A
- cytokines secreted are different for different types of helper T cells
- TH1
- Heavy chain switching to make IgG
- Good opsonin
- TH2
- IgE
- IgM
- IgA (MALT)
21
Q
what term refers to the type of antigen that can activate a B cell without necessarily requiring help from helper T cells?
A
multivalent
22
Q
When do CD8+ T-Cell Divide into Clone?
A
- following its encounter with another cell displaying its specific peptide on an MHC I molecule
- In a lymph node this initial cell is likely to be a dendritic cell
- Termed Cytotoxic T-Cell
23
Q
Cytotoxic T-Cells
A
- look for ordinary cells in the body displaying the specific peptide on MHC I molecules
- Virally infected cells
- Must undergo apoptosis
24
Q
How Cytotoxic T-Cells Induce Apoptosis
A
- TCR to the peptide in the MHC I
- forms an adhesion complex with the infected cell
- Releases secretion vessicles
- Secretion vessicles contain perforin
- forms channels in the infected cell
- Also contain granzyme
-
proteases that activate certain caspases
- Set of enzymes that trigger apoptosis processes
-
proteases that activate certain caspases
- Fas ligand, can also activate caspases via another pathway
25
Q
From lecture, what are some of the things that happen during apoptosis?
A
- The cell tends to detach from whatever it is normally attached to.
- The mitochondria become permeable, releasing their contents into the cytosol.
- The nucleus breaks down, releasing its contents. Nucleases break apart both the cellular and viral nucleic acids.
- Phospholipids in the plasma membrane tend to evert, so that the outside of the cell now has unusual phospholipids on the outside.
- The plasma membrane become permeable and the influx of fluid gives the cell its blebbed appearance.
26
Q
Most Effective Opsonins
A
- antibodies of the type IgG and IgM
- antibody binds to its antigen on a microbe
- Fc region of the antibody binds to an Fc receptor on a neutrophil or macrophage
- Phagocytosis
27
Q
Chronic Infections
A
- Phagocytosis by itself may not be enough to kill the microbes engulfed
- Ex: TB: lysosomes are prevented from fusing with the phagosome
28
Q
What Happens In Macrophage Activated State?
A
- more of the killing factors are synthesized, and the lysosomes are more likely to fuse with the phagosome
- more potent mix is released into the phagolysosome.
29
Q
Complement System
A
- can be activated via antibodies bound to microbes
- either IgG or IgM, especially the pentameric form
30
Q
Which one of the following best describes how a TH1 cell identifies a macrophage to activate?
a. By binding to the macrophage using molecules of innate immunity
b. By its T cell receptor binding to peptide antigen displayed on MHC II molecules
c. By its T cell receptor binding to peptide antigen displayed on MHC I molecules
d. By binding to the macrophage with C3b attached.
e. By the macrophage using a Fc receptor to bind to IgG.
A
B
Good! Helper T cells are CD4+, which means that bind to antigen displayed on MHC II molecules.
31
Q
Eosinophils
A
- have an Fc receptor for IgE
- IgE binds to the cuticle of a helminth
- Fc receptor on an eosinophil can bind to the Fc region on the IgE
32
Q
Mast Cells
A
- found especially under epithelia
- large secretion vesicles filled with paracrine secretions like histamine
- mast cells have Fc receptors for IgE
- multivalent antigen appears again, it causes the the Fc receptors to cluster
- receptors phosphorylate each other
- tyrosine kinase
- exocytosis of the vesicles and synthesis of prostaglandins and leukotrienes
33
Q
Mucosal Immunity
A
- IgA is joined into dimers with a J-chain
- binds to the basal surface of the intestinal or respiratory epithelium
- engulfed by the cell, transported to the luminal membrane, and released into the lumen
- dimeric IgA binds to bacteria or viruses
- prevent their binding to the epithelium
- cause agglutination
- class of lymphocytes found within the epithelium itself
- largely T cells
- majority of the CD8+ variety
- respond to some of the more common microbes in the lumen
34
Q
Mucosal Membranes
A
- secretions such as saliva
- antibacterial enzyme, lysozyme
- antimicrobial peptides such as defensins
- IgA
- dimeric form binds to the inner surface of epithelial cells
- engulfed by the cell by endocytosis
- moves in a vesicle across the cell and is released into the lumen by exocytosis
- IgA prevents binding and causes agglutination, swept away by mucous/body
- epithelium also has lymphocytes embedded in it
- special population that respond mainly to a restricted set of antigens typically found in the lumen of the GI tract and respiratory airways
- Most are CD8+ T cells that kill infected cells
35
Q
Pathogens in Interstitial Spaces, Lymph and Blood
A
- phagocytosis by neutrophils or macrophages is its most likely fate
- most effect opsonin is antibody in the form of IgG (or IgM)
- Agglutination by these antibodies helps phagocytosis
- Complement System
- innate, IgG, especially IgM pentamer
- opsonin C3b, MAC
- C3a and C5a peptides serve as inflammatory paracrines
- helminth worms, eosinophils become involved, especially if IgE is made
- TH2 helper T cells
- Eosinophils have vessicles with basic and toxic proteins
- myeloperoxidase, oxygen radical story
- Mast cells also release inflammatory paracrines
36
Q
Pathogens in the Cytosol of Cells
A
- slow the spread of the infection with IFN-alpha and IFN-beta
- induce in nearby cells an “anti-viral state”
- synthesis of certain proteins that slow viral replication and slow down cell growth and division
- ultimate solution is apoptosis
- caused by natural killer cells of the innnate system and cytotoxic T cells of the specific immune system
- Macrophages then engulf the remains
*
37
Q
Pathogens in vessicles inside cells
A
- “activation” of macrophages by TH1 helper T cells is the next step
- recognizes the macrophage due to antigen displayed on an MHC II molecule
- helper T cell releases** IFN-gamma**
- increases the fusion of lysosomes with the phagosome and increases synthesis of oxygen radicals and other killing mechanisms
- Cytokines are also released that cause inflammation and recruit further cells
- wall off the pathogen through the formation of a granuloma.
38
Q
Table summarizing effector mechanisms and locations
A
39
Q
Ordinary Influenza Infection
A
The virus first binds to and infects cells of the upper airways:
- macrophages phagocytize virus and release cytokines such as TNF-alpha, etc.
- natural killer cells slow the infection
- cytotoxic T cells (CTL) cause virally infected cells to undergo apoptosis
- IgG promotes phagocytosis of any viruses entering the interstitial fluid
- IgA is transfered to the lumen of the airways in order to bind to the viruses and prevent them from attaching to the epithelial cells
40
Q
Secondary Bacterial Infection
A
- person with a compromised immune system, it can lead to bacterial pneumonia
- lung tissue fluid filled at autopsy
- edema, neutrophils and other white blood cells fill the delicate alveoli
41
Q
Hemagglutinin and Neuraminidase
A
- Influenza A has two important surface molecules
- hemagglutinin: binds to the surface of cells in the body, following which the cell takes up the virus and become infected
- neuraminidase: enzyme that cleaves the molecule on the host cell that binds hemagglutinin. Hemagglutinin attachment must be broken for the new viruses to be free to move on and infect other cells.
42
Q
Hemagglutinin and Neuraminidase Types
A
- 16 different hemagglutinin types and 9 different neuraminidase
- Antibodies against one type not effective against another type
43
Q
Influenza A
A
- Bird Virus
- Affect human: H1N1, H1N2 and H3N2
- H5N1 not normally infect humans
- but when does, deadly
- H7N9 also deadly
- doesn’t move from person to person well
44
Q
Antigenic Drift
A
- small variation, which creates a new strain
- hemagglutinin and/or neuraminidase molecules acquire point mutations
- This is why flu appear regularly
- Requires a new vaccine
- Create epidemics of flus
45
Q
Antigenic Shift
A
- Causes **pandemics **
- a new subtype is created
- Flu A: genome is encoded in eight separate segments of RNA
- two different subtypes of influenza A infect the same individual, it is possible for new viruses to wind up with segments of RNA from both sources
- Usually pig/bird with double infection
- antigenic shift occur in H5N1 or H7N9 to make human-human easy, cause a deadly pandemic
- Influenza B cannot undergo antigenic shift
46
Q
Influenza Vaccines and Antiviral Medications
A
- three subtypes that the WHO feels are most important for the year
- This years: protects against an influenza A H3N2 virus from 2012, the H1N1 virus that emerged in 2009 to cause a pandemic, and an influenza B virus
- Intranasal flu vaccine: attenuated, live viruses, which usually work by causing mucosal immunity
- Antivirals against influenza A
- neuraminidase inhibitors
- Oseltamivir (Tamiflu) is taken orally
47
Q
H5N1, H7N9, H1N1
A
- “Bird Flu”
- 2010, for example, WHO identified 40 cases of H5N1, of which 50% were fatal
- H7N9 is fairly similar
- H1N1 subtype known as “swine flu”
- When leads to hospitalization, significant portion of people die
- Dangerous forms that can move deep into lungs and cause** viral pneumonia**
*
48
Q
Bacterial vs. viral pneumonia
A
- Bacterial: virus infects the upper airways
- secondarily cause bacteria to move into lungs
- fluid and neutrophils in aveoli
- Viral: directly infect epithelium lining aveoli
- fluid and cells accumulate in interstital space
- necrosis
49
Q
What causes flu infection to be fatal?
A
- H5N1 causes considerable release of TNF-alpha
- cytokine storm
-
Septic Shock (sepsis: bacteria and toxins, septicemia: only bacteria)
- endothelial permability increase, not enough blood profusion to tissues
-
Disseminated Intravascular Coagulation (DIC)
- clotting factors and platelets depleated
- organ failure due to clots
- TNF-alpha and IL-1, make clots form
-
Acute Respiratory Distress Syndrome (ARDS)
- epithelial inflammation out of hand
- dyspnea and tachypnea
- once develop, mortality 50%
50
Q
Given the seriousness of a potential influenza A (H5N1) pandemic, why aren’t we being vaccinated right now?
A
The antigenic shift/drift has not taken place yet. Cannot create vaccine for an unknown virus
51
Q
Hepatitis
A
- Hep A: acute disorder
- liver cells infected and macrophage/neutrophils cannot get at them
- IFN-alpha and IFN-beta are released by virally infected cells
- Induce an anti-viral state
- Number of processes that lead to release of interferons.
- Toll-Like Receptor and cytosolic protein that responds to RNA
- NKC cause apoptosis of the infected cells
- In one to two weeks, make antibodies, igM and IgG
- cytotoxic T cell: causes the flu like symptoms
- Hep B and C: immune system not good enough to clear out,
- Chronic
- treated with IFN-alpha
- Increases the MHC1 molecules on cell surface
52
Q
Tuberculosis
A
- dendritic cells phagocytosis some of virus
- TH1 helper cells
- lots of antigen and strong stimulation by antigen
- Bind MHC II of macrophage
- IFN-gamma
- greater fusion of the lysosomes with phagosomes, phagocyte oxidase, and the release of cytokines that cause inflammation and recruit further macrophages.
- If not work, additional macrophages, leading to a granuloma
- Bacteria walled off but still tissue damage because helper T cells strongly stimulate the killing mechanisms and promote strong local inflammation
- Granuloma can come back as secondary TB
53
Q
Anthrax
A
- Taken by dendritic cells to lymph node
- Become vegitative and start dividing
- Capsules inhibit phagocytosis
- causes hemorrhagic lymphadenitis, enter blood in large numbers
- Toxins released by bacteria, systemic inflammatory response
- Release oxygen radicals and TNF-alpha and IL-1
54
Q
Ebola
A
- Enters through mucous membrane or break in skin
- macrophages and dendritic cells infected
- virus suppresses type I interferon and divides rapidly
- hypotension and shock
- macrophages synthesis tissue factor and d dimer becomes present in blood
- After three or four days, platlets are low, and bleeding,
- hemorrhagic fevers
55
Q
What type of lymphocyte without T cell receptors causes apoptosis of virally infected cells?
A
Natural Killer Cells
56
Q
Patient B
A
- On day 10 hematocrit is elevated
- Dehydration concentrates the blood
- Collapsed inferior vena cava
- Dehydrated, hypovolemia
- Edema in intestinal walls
- Increased permeability of endothelial
- High C-Reactive protein
- Lots of TNF-alpha and IL-1
- Day 14 or 15
- More WBC and CRP
- Less viral RNA and less diarrhea
- Secondary bacterial infection from crossing compromised intestinal mucosa
- Elevated lactate shows signs of septic shock, mitochondria not recieving enough oxygen
- Epistaxis (nose bleeding) because of thrombocytopenia from platelets in endothelial
- D-dimer levels show fibrin being formed throughout body, DIC
- Increased breathing to offset lactic acidosis
57
Q
Atopic Response (Definition)
A
- Type I hypersensitivity
- Immediate hypersensitivity
- Allergies
58
Q
Sequence in Atopic Response
A
- Antigen called allergen
- Inappropriate formation of TH2 cells
- Small antigens with little inflamation
- Steer towards IgE formation
- Binds Fc receptors on mast cells
- Within an hour
- Secretion of mast cell vesicles
- histamine
- Release eicosanoids
- Leukotriene C4 (anti-eicosanoid and LT drugs)
- Secretion of mast cell vesicles
- Begins in about 2-4 hours
- Cytokine secretion from mast cells
- Notable, TNF-alpha
- Recruits more WBC (TH2, eosinophils)
- Eosinophils release their toxic proteins
- Long-term chronic inflammation
- Treat with glucocorticoids (corticosteriods)
*
59
Q
Anaphalaxis
A
- systemic response to an allergen
- can lead to shock
- uticaria in skin
- mucosal irritation leading to vomiting and diarrhea
- airways swell making it hard to breathe
- penicillin=hapten (reponse after binding to protein in body)
- Epinephrine to raise blood pressure and relax airways
60
Q
CD4+ T cell Activated Macrophages in “Delayed Allergic” Responses
A
- Involves Tcells and activated macrophages
- Second introduction of antigen produces a larger response
- macrophages producing damage
- Contact dermatitis (hapten)
- Langerhans in epidermid carry to lymph node
61
Q
Autoimmune Diseases Due to Antibodies
A
- B-Cells making antibodies
- myasthenia gravis, antibodies bind to and inactivate acetylcholine receptors on skeletal muscle
- IgG or IgM
*
62
Q
autoimmune thrombocytopenia
A
Antibodies bind platelets and lead to destruction
63
Q
Graves disease
A
- B-cells secrete antibody that binds to a protein
- Stimulating antibody bind to TSH receptor
- Release thyroid hormone
- Goiter
64
Q
Rheumatic fever
A
- antibodies produced to act on a pathogen
- streptococci cross-react with molecules in the body
- Damage to heart muscle and valves
65
Q
systemic lupus erythematosus (SLE)
A
- complexes of the antibody and antigen
- young women
- makes antibodies against a number of molecules in the nucleus
- Complexes of the antibody and antigen form and cause damage as they are deposited in tissues
- glomerulus of the kidney
- skin and joints
- sun exposure leading to rash
66
Q
Autoimmune Disorders Involving T cells
A
- T cells release cytokines that can cause inflammation directly or activate macrophages
- Inflammation is a central feature of these disorders and fits the chronic type pattern
- blocking TNF-alpha is an effective treatment
*
67
Q
Antigen Spreading
A
- additional self-antigens become involved in the response
- as attacked, more self antigens exposed, to which the immune system might respond
68
Q
In addition to cytokines, such as TNF-alpha, what are some of the factors that activated macrophages release?
A
enzymes, growth factors, oxygen radicals, NO
69
Q
rheumatoid arthritis
A
- immune system attacks the synovial membrane
- synovial inflammation and destruction of joint
- early, bilateral stiffness
- nodules on bony areas where lots of movement
- synovial membrane inflammed
- hyperplasia and creates finger like extensions
- angiogenesis leading to abnormal structure, pannus
- destroys the joint
- pannus may extend over destroyed joint, leading to ankylosis
88
Q
Facilitated Diffusion
A
- carrier protein with specific binding site for molecule
-
Glucose Transporter
- Glucose Uptake
- specific binding site for glucose
- Concentration gradient determines rate of uptake
- Does not require ATP
- Control transport by controlled number of transport proteins in the membrane
- Low insulin, few glucose transporters
- High insulin, more glucose transporters
89
Q
Coupled Transport
A
- two substances are required to bind in order for transport to occur
- Free energy driving the transport is the sum of the free energies for transport of both substances
- If it is in the same direction, it is called cotransport
- If it is in the opposite direction it is called countertransport
91
Q
Saturation
A
- facilitated diffusion and coupled transport show saturation
-
transport maximum (Vmax)
- every transporter is bound by substance
- transport rate cannot increase
93
Q
ABC Transporters
A
- that depend upon ATP binding for transport
- ATP-Binding Cassette
- two nucleotide binding domains that bind ATP
- Ex: multidrug resistance protein (MDR1)
- pump a wide variety of nonpolar drugs and toxins out of cells
- resistance to chemotherapy in cancer cells
- Ex: CFTR
- forms a Cl- channel that is expressed on the apical plasma membrane of many epithelial cells.
- Defective in cystic fibrosis
- decreased secretion
- ion channel that is regulated by both phosphorylation and ATP binding
- bacterial toxins causing unregulated activity can lead to diarrhea
95
Q
Voltage Gated Sodium Channels: Organization
A
- 24 transmembrane domains
- 4 clusters of 6 TMD
- Each group of 4 is a homologous domain
- Clustered to form a channel in the middle
97
Q
Voltage Gated Sodium Channel: gate
A
- gate opens in response to regulatory molecules that specifically bind to either the inside or outside
- gate is controlled by a voltage sensor, which responds to the level of the membrane potential.
- several voltage sensors must respond before the gate opens
- inactivation gate limits the period of time the channel remains open
99
Q
Know these parts of intesine
- Lumen
- ECF
- Tight Junctions
- Apical membrane
- Basolateral membrane
- microvilli
- different sets of transporters are localized in either the apical or basolateral membranes
A
100
Q
Epithelial: Absorption
A
- Glucose across the apical membrane by sodium-glucose cotransporter
- Na+ gradient is established by the Na+/K+-ATPase
- located on basolateral membrane
- Facilitated diffusion of glucose into the ECF is a passive process
- glucose transporter
102
Q
Epithelial: Secretion
A
- solutes are moved across the epithelium, which then draw water into the lumen by osmosis
- rate-limiting and regulated step in intestinal secretion is the movement of Cl- ions across the apical plasma membrane
- Cl- is transported into the epithelial cell by a cotransporter expressed on the basolateral membrane
- Na+ gradient, established by the Na+/K+-ATPase
- Cl- down concentration gradient via Cl- channel CFTR
103
Q
CFTR
A
- member of the ATP-binding cassette (ABC) protein family
- ATP binding is used to open an ion channel
- regulatory domain that is phosphorylated by protein kinase A (PKA), also known as cAMP-dependent kinase
- alpha subunit of the G-protein to activate the enzyme adenylyl cyclase
- Adenylyl cyclase produces the second messenger cAMP which activates PKA to phosphorylate CFTR
- cholera toxin chemically modifies the alpha subunit of the G-protein so that it cannot inactivate
108
Q
Calcium
A
- 2nd messanger because cellular concentrations are kept very low
- exocytosis of secretory vesicles
- regulation of contraction
- One source of Ca++ is from the ECF
- ER, or the sarcoplasmic reticulum in muscle cells
- Ca++ released by second messanger inositol triphosphate (IP3)
- binds to ligand-gated Ca++ channels
- signal is rapidly terminated by Ca++-ATPases
- transport Ca++ out of the cytosol
111
Q
GPCR Activation
A
- GPCR associate with trimeric G-proteins
- alpha, beta, and gamma subunits
- Exchange GDP for GTP at alpha
- Dissociates into alpha and beta-gamma
- Alpha diffuse along membrane and activate enzymes to make second messangers
- Beta-Gamma diffuse along membrane and activate ion channels
- Inactive by alpha-subunit intrinsic GTPase activity
- With GDP, can reassociate with the beta-gamma complex
- Cholera toxin causes a chemical modification that prevents GTP hydrolysis and leads to unregulated signaling
112
Q
Adenylyl Cyclase
A
- catalyzes the formation of the second messenger cyclic AMP (cAMP)
- generate many molecules of cAMP
- amplify the signal
- bind to and activate protein kinase A
- PKA then phosphorylates target proteins in the cell
- cAMP is rapidly broken down by phosphodiesterases
- Cholera toxin
- destroys GTPase activity of G-alpha
- persistant adenylyl cyclase activity
- continuous cAMP
- continuous activation PKA
- Continuous phosphorylation of CFTR
113
Q
Phospholipase C
A
- cleaves PIP2
- generate two second messengers, IP3 and diacylglycerol (DAG)
- IP3 (water soluable) binds and open ligand-gated Ca++ channel
- DAG (lipid soluable) activates protein kinase C (PKC)
114
Q
Desensitization
A
- G-protein Receptor Kinase (GRK)
- Phosphorylates on GPCR
- Beta-arrestin binds and prevents trimeric G-protien from associating
- BA targets GPCR for endocytosis
- receptor downregulation
115
Q
JAK Mechanism of Signaling
A
- regulatory molecule binds and brings two receptor molecules together to form a dimer
- phosphorylate each other
- activates JAK, allowing it to phosphorylate the receptor
- phosphotyrosine residues on the receptor proteins are binding sites for STAT proteins
- Signal Transducer and Activator of Transcription
- considered latent transcription factors
- phosphorylated by JAK
- Dimerize
- binds to specific sequences in the DNA
- Inactivation occurs when phosphatases remove phosphate groups from various proteins in the signaling pathway
116
Q
Molecules that work through JAK-STAT Signaling
A
119
Q
Receptor Tyrosine Kinase Steps in Signaling
A
- ligand binding causes receptor dimerization
- receptor autophosphorylation: receptors phosphorylate each other
- phosphotyrosine binding site for adaptor protein
- adaptor protein bound to a guanine-nucleotide exchange factor (GEF protein)
- GEF activates Ras, small monomeric G-binding protein
- GTP replaces GDP
- cascade of protein kinases
- phosphorylation of transcripition factors
- Ras control cell proliferation
- other monomeric G-proteins involved in
- Cell shape through effects on cytoskeleton
- involved in membrane trafficking through exocytosis and endocytosis
126
Q
molecular structure of a nuclear receptor
A
- Three important domains
- transcriptional regulation domain
- DNA binding domain
- ligand binding domain.
129
Q
NO
- uses
- how it synthesized/signals
A
- Neurotransmitter
- Paracrine
- relax smooth muscles in blood vessels
- Synthesis:
- nitric oxide synthase(NOS) is activated
- enzyme acts on an amino acid (L-arginine) to create nitric oxide
- Three forms NOS
- phagocytes, neurons, and endothelial cells of blood vessels
- NO diffuses to and activates a guanylyl cyclase
- soluable, cytosolic GC
- Guanylyl cyclase converts GTP to cyclic GMP
- cGMP acts as a second messanger
132
Q
autonomic nervous system organization
A
- The cell body of the preganglionic neuron is in the central nervous system
- the cell body of the postganglionic neuron ia found outside the central nervous system in an autonomic ganglion
134
Q
Neurotransmitters and Receptors
- Para/Symp Pre and Post ganglion
- Neurotransmitter release
- Type of receptor activated
A
135
Q
Ex: Autonomic Control of Heart Rate (Sympathetic)
A
- Speed heart rate
- preganglionic neurons are found in the lateral horns of the first five thoracic segments (approximately)
- axons of these neurons then project to the sympathetic ganglion chain (mainly in this case the inferior cervical ganglion) lying just outside the vertebral column
- in the ganglion the preganglionic neurons form synapses with the postganglionic neurons
- axons of the postganglionic neurons then project out of the ganglion and approach the heart along the large blood vessels connected to the heart
- spread over the surface of the heart before penetrating into the heart muscle tissue.
136
Q
Ex: Autonomic Control of Heart Rate (Parasympathetic)
A
- Slows heart rate down
- the cell bodies of the preganglionic neurons are in the brainstem (medulla)
- axons project out via the vagus nerve
- next to the heart, on the superior surface, are the cell bodies of the postganglionic neurons
- postganglionic axons are short, and project a short distance to the special cardiac muscle fibers near the top of the heart that control the heart rate.
*
137
Q
Ex: Autonomic Control of Pupil (Sympathetic)
A
- Dialates
- cell bodies of the sympathetic preganglionic neurons again are in the lateral horns of the upper thoracic segments, but project mainly to the superior cervical ganglion of the sympathetic chain ganglia.
- In the ganglion are the cell bodies of the postganglionic neurons, and their axons then project up to the head and then through the superior orbital fissure and into the eye.
138
Q
Ex: Autonomic Control of Pupil (Parasympathetic)
A
- Constricts
- cell bodies of the parasympathetic preganglionic neurons are in the brainstem (midbrain) and their axons project out in the oculomotor nerve, which passes through the superior orbital fissure.
- On the other side of the fissure is the ciliary ganglion, which contains the cell bodies of the postganglionic neurons. Axons from these neurons then proceed to the iris.
164
Q
efficacy
A
- refers to the range of effects of ligand binding on receptor activity
- and thus, biological response
- partial agonist
- do not produce the maximal biological response
- antagonists
- drugs that bind the receptor and prevent activation
- inverse agonists
- Drugs that inhibit basal activity
