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74 Cards in this Set

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  • Back
What are hormones?
Chemical messegers that transport signals from one cell to another through the bloodstream
What are the major hormone producers?
Pineal gland, ovaries, testes, thymus, thyroid gland, pituitary gland, adrenal gland
What are the two types of hormones?
What are the differences between polypeptide hormones and steroid hormones? Examples?
Polypeptide hormones: polar, water soluble, hydrophilic, large proteins. Ex: Epinephrine/dopamine (amino acid derivatives)
Steroid hormones: apolar, hydrophobic, water insoluble Ex: testosterone, estrogen (cholesterol derivatives) Need a carrier to go trough the blood
What is the method of action for peptide hormones?
Hormone binds receptor on the cell, causes a conformational change of the receptor, activates 2nd messenger. Get a signal cascade and 2nd messenger will enter nucleus and alter gene transcription
What is the method of action of Steroid hormones?
Diffuse across the cell mb, where they interact with cytoplasmic factors, which transport them or make them soluble. They end up in the nucleus and bind nuclear hormone receptors. Fct as TF
Which hormone is faster acting? Why?
-Peptide hormone.
-Meet their receptor earlier and cause rapid cascade (instead of ghaving to diffuse across the mb)
What are the hormone classifications (3)?
1) Endocrine: Source far away from target
2) Paracrine: Source close to target
3)Autocrine: act on same cell or same cell type
What are the mechanisms of action for signal transduction? (4)
1) Specificity: Hormones very specific. One molecule for one receptor. Receptor has very high affinity for its ligand. Also cooperativity and amplification between the ligand and the receptor (small change in [ligand] drastically changes receptor activation)
2) Amplification: activation of downstream effectors. Small change in conc causeshuge cascade
3)Desensitization: Negative feedback signal. Output signal: response from hormone binding receptor can turn off the hormone
4) Integration:2 dif hormones activate 2 dif paths that work tog to modulate a response
What are the different receptors that mediate the mechanism of action of teh hormones? (6)
1)Gated ion channels
2)Receptor Enzymes
3)GPCR/Serpentine receptors
4)Steroid receptors
5)Receptor w/ no intrinsic enz activity
6) Adhesion Receptors
What are two methods to measure hormone concentration?
What does RIA involve?
-Need radiolabelled hormone and specific antibody
-have unknown [hormone] and perform binding competition btw labelled and unlabelled hormone to a known amount of antibody.
-Plot a standard curve using unbound:bound ratio
What is RRA?
What can it be used for?
Same as RIA, but uses a receptor instead of an antibody
-Can be used to determine the [hormone], the receptor density and the affinity of the receptor for its hormone
What ae the three major types of experiments? Describe them.
1)Kinetic: Measures the association and dissociation rate constants
R + L<---> RL
K1 (K on): depends on [unbound hormone] and [unbound receptor]
K-1 (K off): depends on bound RL complex
2)Saturation:Measure max binding and diss't constant (Kd)
Kd=(K off)/(K on)=[R][L]/[RL]
Smaller the Kd, higher the affinity of the ligand for its receptor
Kd= [] at which 1/2 the binding sites are occupied
3)Inhibition: determine Ki
Ki= [inhibitor] at which 1/2 of the receptor sites are occupied by the inhibitor
Describe the Scatchard plot.
-Slope= -1/Kd
-X-intercept= Bmax (receptor density)
Y= -B/Kd + Bmax/Kd
When is the Scatchard plot linear? Curved? Examples.
Linear: when binding of hormone to receptor is independent (independent receptor site)
Curved: can be positive or negative curve. Indicates cooperativity
Positive curve: binding of hormone to one receptor, increases the receptor's affinity to attract other hormones (Hb and O2)
Negative curve: binding of hormone tothe receptor decreases the receptor's affinity for other hormones (Insulin)
What is diabetes?
Insullin resistant syndrome
What is the difference between type I and type II diabetes?
Type I: Insulin dependent, pancreatic cells don't produce enough insulin
Type II; Insulin independent. Can be making enough insulin, but insulin receptors are insensitive to insulin and don't recognize it. Type II is considered a disorder of FA metabolism
How can you mediate type I diabetes? Type II?
Type I: Insulin shots
Type II: Weight loss/exercise
What is Hypoglycemia shock?
Overdose of insulin, body's cells takes up too much glucose to quickly, not enough glucose left in the blood
What are the targets of glucose for storage?
Fat cells
Liver cells
Muscle cells
What are some properties of Insulin?
-Secreted in response to high [glucose]
-Enhances glucose transport from blood to body cells
-Stimulates glycogen synthase
-Inc oxidation of glucose to CO2
-Enhances ptn synthesis
-Blocks gluconeogenesis (inhibits Pyruvate carboxylase and fructose diphosphate)
-Works at very low concentrations
-Interacts w/ insulin receptor
How is insulin processed?
-Starts as preproinsulin
-Preproinsulin's signal seq is cleaved by proteolysis to become Proinsulin
-Proinsulin is stored in the pancreatic cells
-Proinsulin is cleaved to get mature form of insulin
In what form is insulin stored?
What form is it active in?
Stored as a Hexamer (cuz its more stable, stabilized by a Zinc molecule)
Active as a monomer
Describe the Insulin receptor.
-Heterotetrameric tyrosine kinae receptor.
-2 extracell. alpha subunits, held tog by di-S bonds
-2 beta transmb subunits that have phosphotyrosine kinase activity'
-Has CR, KD, JM and CT domains
CR: binds insulin at alpha part
of receptor
JM: P sites
KD: kinase domain, gets P
CT: also gets P
Describe the negative cooperativity of insulin binding its receptor.
-When RIA performed, got curved scatchard plot
-insulin initially binds receptor with high affinity
-Max bio. response when 2% of receptors are bound (when more then this, binding becomes much less efficient)
Why is the max biological response only 2%?
-Glucose uptake=fast response
-want to slow down glucose uptake to counteract rapidity of this response otherwise can get hypoglycemic shock
.: need lots of spare receptors to have efficient insulin binding
How does negative cooperativity affect people with type II diabetes?
Ppl with type II already have low amt of receptors, so when just a little insulin in the blood, already surpass the 2%,insulin receptors are locked in low affinity conform.
How does insulin induce negative cooperativity through binding?
Insulin binds the two alpha chains assymetrically (binds site 1 on a1 and site 2 on a2) this disrupt the molec so receptor can't accept more insulin. cnfor change in a leads to conf. change in beta
-first binding with high affinity
-subsequent bindings=low affinity (cuz first binding pulls the 2 a-chains apart)
What happens when insulin binds the insulin receptor?
-Auto-P of 3 tyrosines in the kinase dom of the beta chain
-active site is stabilized and opened
-other tyrosines are P i the insulin receptor and downstream targets
Whattype of downstream events does insulin activate?
-Metabolism: glucose transport and glycogen synthesis
-Cellular growth and differentiation: RNA/DNA/Ptn synthesis
What is IRS-1? What are its domain?
Insulin receptor substrate-1. Has a role in mediating the effects of intracellular insulin
-PHD:anchors IRS-1 to mb
-PTB: Interacts with Y190 when its P, localizes it to insulin receptor
-C-terminus: has multiple Tyrosine P sites that are docking sites for SH2 domain containing ptns
How is IRS-1 activated?
How does it activate glucose uptake?
1)Tyr 960 (of JM) is P
2) 3 sites on KD are P (stabilize and keep KD open)
3)P of JM recruits IRS-1 thru PTB, which can then be P on 5 sits by KD (these P sites used to recruit other ptns)
4) IRS1-P recruits p85a of P13k which will bring catalytic subunit p110 (p110+p85=P13k)
5)P13k P PIP@ and makes it PIP3
6)PIP3 gets PKB
8) PKB-P recruits glucose transporter
10)GSK3-P cant P glycogen synthase .: gluc-> glycogen
11)PKB stimulates mov't of vesicles to alow shuttle of glucose into the cell
How does insulin activate/regulate gene transcription?
1)Insulin binds its receptor, which auto-P on tyr residues
2)Insulin receptor P IRS-1 on its tyr residues
3)Grb2 recog. other 3 P sites on IRS-1 and binds. Grb2 ass't w/ SOS, which kicks out GDP for GTP and acivates Ras
4)Ras activates Raf
5)Map kinase path... eventually ERK-P, translocates into nucleus where it P SRF and Elk1
they dimerize and turn on DNA syn
How can the insulin receptor be regulated/turned off?
1) Neg. fdbck, serine/threonine kinases turn off insulin receptor
2)Receptor mediated endocytosis: degrades receptor
3)Recycle the receptor
How is glucose transported into RBC?
1)GLucose binds to extracell part of GLUT1
2)Conform change of GLUT1
3)Outside of GLUT1 closes and inside opens
4)Glucose is transfered into the cell
What happens to GLUT1 when insulin is present? Absent?
When insulin is present, GLUT1 migrates to plasma mb
When insulin is absent, GLUT1 remain in the cell
How do glucose transporters work?
1)They're initially stored in cytosolic vesicles
2)Insulin binds receptor and transporter fuses with the mb
3)When glucse lvls dec, inslin lvls dec and transporters are recycled or degraded
Does insulin increase exo or endocytosis of glucose transporters?
Inc exocytosis of GLUT4 by 10-20 fold (and also dec its endocytosis)
What are the 3 main kinases thatmediate glucose transport?
What does the lipid raft do?
Stabilizes the signalling complex
Wht is GLUT2?
Glucose transporter in the B-islets of Langerhams cells in the pancreas.
When lots of glucose in the blood, GLUT 2 stimulated, leads to excretion of insulin
What does insulin activate?
1)Recruitment of glucose transporters (series of P, including PKB and PDK1)
2)other paths, including the regulation of lipid rafts using caveolin and flotilin
When insulin levels are high, how is glucose stored?
1)Glycogen (muscle and liver)
2)TAG: triacylglycerol (adipose tissue)
WHat is the counteracting hormone to insulin?
What makes glucagon?
alpha islet of Langerhans in the pancreas
What does glucagon do?
Stimulates glucose synthesis and glycogen breakdown in the liver
(glucagon released when low levels of glucose in the blood)
What happens durig starvation?
-Liver becomes main source of glucose
-Glycogen in the liver is broken down. G1P-> G6P-> glucose
-Ptns and TAG degraded and used in gluconeogenesis
-Excess acetyl CoA i transported out of iver to be made into ketone bodies (i.e. for the brain)
What determines if glucose will be produced or degraded in the liver? How?
-Ratio of insulin to glucagon
Itcontrols rates of gluconeogenesis and glycogenolysis?
Describe GPCR.
-Hepta helica transmb receptor
-Binds heterotrimeric G-ptn (which has alpha, beta and gamma subunits)
-When glucagon binds, G-ptn is recruited to GPCR and exchanges GDP for GTP
-G-alpha subunit can vary:
->Gs:stimulates adenylyl cyclase to get cAMP
->Gi:inhibis adenylyl cyclase
->Gq: stimulates phospholipase C
What is epinephrine?
-aa derivative hormone
-not a peptide hormone
-hormone and NT
--als known as adrenalin, fight or flight response
How does epinephrine act?
Breakdown glycogen in the liver and release lipids from fat cells to inc glucose lvls
Describe the epinephrine receptor.
-Beta adregnic receptor
-Also a GPCR
-hepta transmb helices
-when epinephrin binds, G-ptn recruited to the GPCR
How is the epinephrine signal transduced?
1) Epinephrine binds its receptor
2) Gs-GDP => Gs-GTP (active)
3) Gs activates adenylyl cyclase
4)Adenylyl cyclase causes conversion of ATP to cAMP
5) cAMP activates PKA
6) PKA P cell ptns and causes a cell response
7) cAMP is degraded, stopping the response, no more active PKA
How are the glucagon receptor and epinephrine receptor (adrenergic receptor) related?
-Effects of gluagon and epinephrine are additive (tho both receptors are found in different proportions)
-High epinephrine and glucagon leads to rapid glyconeolysis and .: glucose is released
How is PKA regulatory?
-P glycogen synthase and inhibits it (.: don't synthesize glycogen)
-P phosphorylase kinase and activates it.
-Phosp. kinase-P P glycogen phosphorylase, making it active so glycogen can be degraded to glucose.
What is receptor desensitizaion?
Receptor will stop responding after prolonged exposure to its hormone
How is the B-adrenergic receptor desensitized?
1)Epinephrine binds its receptor, causing Gs to diss't from the Gs/B/gamma
2)Free GsB/gamma recruits the B-adrenergic receptor kinase (BARK) which blocks further binding of G-ptns at the receptor and also P 2 serine residues on the receptor
BARK recruited cuz of Gs: prod adenylyl cyclase: ATP-> cAMP, activates PKA, P BARK
3) B-arrestin is recruited. It blocks further ass't with G-ptns and it induces endocytois of the B-adernergic-receptor
4)Arrestin allows receptor to diis't, be de-P and returned to the cell surface
What is leptin important for?
Appetite and weight (energy metabolism)
Satiety hormone
How is leptin affected in ob/ob mice? In db/db mice?
ob/ob: Leptin is mutated, since when paired with any other mice, they lose weight
db/db: Leptin receptor is mtated, since when paired with any other mice, still couldn't lose weight
=>defect in db or ob gene leads to obesity
Properties of Leptin.
-Protein/peptide hormone
-produced mostly by fat cells
-fct: regulate storage of fuel
-ssensed by hypothalamus
What happens when adipocytes taking p a lot of FA?
-Adipocytes get bigger and this is sensed by leptin
-leptin interacts with its receptor in the hypothalamus and tells brain to stop eating
-Leptin inhibits FA synthesis
-Leptin activates FA oxidation
-Adipocyte size starts to dec, .: produce less leptin
-Stomach releases another hormone that says fat stores have been used up
Wht processes does leptin effect?
Metabolism (thru FA oxid)
What are some properties of Leptin?
-prevents accumulation of non-oxid FA
-Protects vs lipotoxicity
=> generates antilipogenic hormone that stops prod'n of lipids
-Prevents loos of fct/viability due to too much fat
What's the difference between the insulin receptor and the leptin receptor?
LR does not have intrinsic Tyr kinase activity, must recruit a kinase
Which tyrosine kinase does leptin recruit?
What is the mechanism of leptin signal transductiokn in the hypothalamus?
1)Leptin binds LR and causes dimerization, which recruits JAK kinases
2)When JAKs are close, they auto-P each other
3)JAK-P then P the LR
4)STAT is then recruited to the P-part of LR. (STAT has SH2 domain, which binds phosphotyrosine residues)
5)STAT is then P by JAK-P
6)STAT-P travel through cytosol as homo/hetero dimer
7)Translocation of STAT into the nucleuswhere it acts as a TF and activates specific genes
How do insulin and leptincooperate to reduce food intake?
-Leptin makes liver and muscle cells more sensitive to insulin
-Cross talk btw insulin kinases and leptin kinases
(Letin-LR activates JAK; Insulin Receptor has its own kinase activity. Both kinases can P IRS2, which goes on to activate PIP Kinase => inhibition of food intake and incorporaion of glucose inside the cells)
What kind of receptor is the nicotinic acetylcholine receptor?
Ligand-gated receptor
What is Acetylcholine?
-NT in nervous system
-Acts on neurons and muscle cells
-Activates nicotinic acetylcholine receptor
-Released by motor neurons
How does acetylcholine work?
-Released from motor neuron
-Diffuses acroos synaptic cleft
-Hits dendrites and binds nic.acetylcholine receptor
-triggers conform. change in receptor, get depolarization and then muscle contraction
Which ions are involved in the response of the acetylcholine receptor to Ach?
Na+, K+, Ca2+
Describe the nicotinic ACh receptor.
-It has 5 subunits (2 identical alpha, 1 beta. gamma, delta)
-4 transmb helical segments (M1-M4)
-M2 helices are amphipathic and interact with charged ions
-M2 helices always point inwards so +-ions can pass thru
-M1,3 and 4 are hydrophobix and stay on the inside, deal with lipids
What happens if you don't have fctnal ACh receptors?
Diseases: paralysis, stiff muscles