Biochem Hormone Action 2 Flashcards
How do you define potentcy
Graph with hormones with different potencies for a R or receptors with different potetcies for a hormone
within a class of hormones, different lignad molecules may have different POTENCIES, represented by EC50 values
The -log[hormone] at which 50% maximal response is elicited
If ther eis higher potentcy, is midpoint (EC50) increacing potency to left or righ?
Left!
Need lower concentration to elicit 50% maximal response
what happens if constant concentrtion of an ANTAGONIST is added?
the binding curve for the hormone (agonist) will shift to the RIGHT
How do you define EFFICACY on graph
Agonist vs PARTIAL AGONIST
Height of response (maximum is 100%)
Agonist will hve response with 100% efficacty (height of response)
PARTIAL AGONIST which only have 50% maximal response, or 50% efficacy (regardless of hormone concentration)
Efficacy vs Potency
Efficacy = height
Potency = midpoint EC50 (concentration of hormone required for half-occupancy of receptor)
depends on both affinity and efficacy
What are the differnt kinds of Regulations of Receptors (3)
Down Regulation
Covalent Modification
Up Regulation
Down regulation
Desnsitization- Ineternalization of R
loss of receptor number from pPM by sequestration. This change results in DESENSITIZATION of biological response to addition of more agonist.
examples of hormones that down regulate receptors
Insulin Glucagon TRH GH LH FSH catecholamines
Covalent modification of the receptor . Example?
Desensitization- frequely Phosphorylation
No change in R number and no translocation occurs.
Hormone binding and effector activaiton systems are uncooupled by covalent modification
I.E. Beta Adrenergic system
Up Regulation
Angiotensin II and PROLACTIN
increase their R number as R on the cell surface become occupied
Types of Hormone/Receptor/Diseases
Abnormal Receptor Regulation
Inadequate production of hormone
Antibodies directed against a specific hormone
No hormone binding to the R can be detected
What are examples of Antibodies directed against specific hormone
Graves Disease
Acanthosis Nigrans (insulin resistant)
Myasthenia Gravis
Asthma
Graves Disease
Ab stimulates TSH R
Hyperthyroidism
Acanthosis Nigrans
Ab blocks insulin binding
insulin resistant
Myasthenia Gravis
Ab enchances turnover of Ach R
Asthma
Ab blocks Beta-Adrenergic binding to R
Examples of diseases where there is abnormal Receptor Regulation (2)
- Obesity - insulin binding is decreased
2. Diabetes mellitus- some form of NIDDM, TYpe II. Insulin binding is decreased; receptor down regulation
Examples of Disease where THERE IS INADEQUATE PRODUCTION OF HORMONE (4)
- Diabetes Mellitus (insulin-dependent form)
- Dwarfism- Deficiency f GH or somatotropin
- Gigantism, acromegaly- Excess secretin of GH
- Familial Neurohypophyseal diabetes insipidus (FNDI)- mUtations in vasopressin prohormone decrease VP syntehsis
FNDI
mutations in vasopressin prohormone decreases VP synthesis
-due to inadequate production of hormone
Diseases where NO HORMONE BINDING TO THE RECEPTOR CAN BE DETECTED (receptor deficiency) (2)
- congenital neprhogenic diabetes insipidus
Pseudohypoparthyroidism
Congenital Neprhogenic Diabetes Insipidus
ADH receptor deficiency
Pseudohypoparathyroidism
PTH receptor deficiency
Classification of hormones by mechanism of action (2)
Hormones that bind to intracellular receptors
Hormones that bind to cell surface receptors
What kind of hormones bind to intracellular receptors?
Usually Steroids estrogen glucocorticoids mineralcorticoids progestins calcitrol (vit D) andorgens thyroid hormones (T3 and T4) Retinoids
What kind of hormones bind to cell-surface receptors (4)
- 2nd messenger is cAMP
- 2nd messenger is Ca2+ and Phosphatidylinositase
- Intracellular effect is a kinase or phosphatase
- Messenger is NO
Types of intracellular hormones (general) 3
Steroids
Iodothryonines
REtinoids
Types of cell surface hormones (general) 4
Polypeptids
porteins
glycoporteins
catecholamines
Solubility of nuclear vs PM hormone
Lipophilic vs hydrophilic
PM transport protein needed in nuclear or PM?
nuclear- yes
PM- some
Mediator of nuclear vs PM
nuclear- receptor-hormone complex
PM
cAMP, P-inositides, kinases, Ca2+ , etc
Mechanism of action of Intracellular (nuclear R) Hormones
- Hormone delivery to cell passes membrnaes
- binds receptor in nucleus
- Activates gene Transciption
- Protein/enzyme levels increase
Do steroid hormones need to be bound to carrier when passing PM?
NO! b/c lipohphilic
What happens when steroid-type hormone binds to an intracellular R ?
intracellular R changes conformation- to homodimer or heterodimer
Complex binds to HRE (hormone response element)
What happens when hormone-receptor complex binds to HRE
complex binds to specific sequence which results in the Tx of a limited set of genes containing the right upstream regulatory elemnts
Three features of Cell Surface Receptor Binding/Cascade
Amplification
Reversibility
Rapidity
How many subunits is the G protein made up of?
three!
Alpah, beta, gamma (different combinations of different types)
In the “resting state”, the trimeric Gs protein has what bound to it? GTP or GDP?
GDP
upon interaction wih occupied R, Gs protein does what
exchanges GDP for GTP, it dissociates and alpha,s-GTP subunits is then capable of activiating the cyclase
How is this system shut off?
By hydrolysis of GTP to GDP by slow, intrinsic GTPase actiity of alpha-s prtein
what has GTPase activity>
alpha-s, reforms Gs protein with GDP bound to alpha subunit
What protein speeds up process of GTP inactivation?
GAP
GTPase activating protein, speeds up process by increasing rate of GTP hyrolysis
noe that alpha-i alos has intrinsic GTPase activity
What is GNEP?
guaninie nucleotide exhchange protein
protein that catalyses reactivation of alpha-i, wich requires an exchange of GTP for GDP
Summary of events for second messenger of cAMP
Events coupled to G-protein
- hormone binds to 7-serpentine R
- The R activates a G-protein by GTP exchange
- Activated alpha-subunit activates adenylyl cyclase
- Adenylyl cyclase produces cAMP form ATP
- cAMP activates protein kinase A (and others)
What is the effect of Cholera Toxin?
it activates G-alpha-s (inhibits GTPase)
irreversably activatves ADENYLATE CYCLASE by preventing GTAse activity of G-alpha-s subunit –> increase cAMP activity –> activates PROTEIN KINASE
What are clinical effects of Cholera Toxin
Diarrhea!
stimulation of active transprot which leads to massive loss of Na ion and water by gut
What is the biochemical cause of cholera toxin
ADP-ribosylation on Arg residues of the G prtein whcih the NAD moleucle provides the ADP-ribose
Cholera = CS = cas (alpha s)
What happns when ADP is ribosylated Gs
GTPase activity is inactivated
Gs constantly activates Adenylate Cyclase
What is the cause of Pertussin Toxin
inhibits G-alpha-i (blocks GTP on
What is clinical effects of Pertussin Toxin
DIAHHREA!
irreversibily activates adenylate cyclase by promoting ADP-ribosylation of alpha-i, which prevents alpha-i subunit form being activated
pertussin = pi (for alpha i)
What are initiating signal (hormones) for G-alpha-S class?
Downstream signal
Beta adrenergic amines
glucagon
parathyroid hormone (PTH)
others
Dwnstrm signal: Stiulate Adenylate cyclase
What hormones serve as initiating signal for G-alpha-i?
Whas is the downstream signal
Acetycholine
alpha-adrenergic amines
NTs
Downstream sgl: Inhibits adenylatec cyclase
What are initiating signals of G-alpha-q? Downstream signal?
Acetylcholine
alpha-adrenergic amines
many NTs
Downstream: Increases IP3 and intracellular Ca
What are initiating factor of G-alpha-t
Photons
Stimulates cGMP phosphodiesterase
G alpha 13
Thrombin
Stimulates Na/ H exchange
Describe activatino of protein kinase A (PKA or camp-dependent protein kinase)
PKA is activated by any mechanism that activates cAMP
CaMP binds to regulatory subunit and causes dissociation of catalytic subunit of PKA
Function of PKA
phosphorylates a wide variety of proteins: (enzymes, membrane proteins, nuclear proteins)
Residues that are phosphorylatd are Ser or Thr residues (NOT tyrosine)
How can PKA system be turnef OFF?
cyclica AMP PHOSPHODIESTERASE
what kind of agents inhibit phosphodiesterase?
METHYLXANTHINES like coffee or theophylline)
amplifies response by preventing or slowing the destruction of cAMP
treats asthamticsby raising intracellular cAMP which leads to relaxation of SM
How can the adrenergic receptor be “desensitized”
by phosphoyraltion by a specific kinase, BARK
for beta adrenergic receptor kinase
B-arrestin then binds to this phosphoyralted domain
Process if Epinephrine is stimulus
B-adrenergic R
Gs
Ad Cyclase
Glycogen breakdown
Serotonin
Serotonin R
Gs
Ad cyclase
Behavrioal sensitization and learnign in APLYSIA
Light
rhodopsin
Transducin
cGMP PDE
Visual excitation
Odornats
olfactory R
G olf
Ad cyclase
olfaction
fMET
chemoatactic R
Gq
PLC
Chemotaxis
Ach
Muscarinic R
Gi
K+ channels
Slowing of pacemaker activity
What does Ras do?
Regulates CELL GROWTH through serine-threonine protein kinases
What does Rho do?
REORGANIZES CYTOSKELETON through serin-theronine protein kinases
What does Arf do?
Activates ADP-ribosyltransferase of the cholera toxin A subunis;
regulates VESICULAR TRAFFICKING pathways; activates phospholipase D
What does Rab do?
Plays a key role in SECRETORY and ENDOCYTOTIC pathways
What does Ran do
Functions in the TRANSPORT of RNA and protein into and out of nucleus
What is neurofibromatosis
variety of benign and malignant tumors of CNS and PNS
dominantly inherited genetic disorder
cuause of Neurofibromatosis
deletion or loss of function mutation in the nfl gene
What are clinical signs
cafe au lait macules (spots)
What is Neurofibromin
GTPase activating protein (GAP) for Ras (and other smll G-proteins)
What happens with loss of neurogbromin?
loss of GTPase activity which inactivates Ras and tehrefore Ras stays on in its GTP-bound form
What is Nf2?
tumor suppressor gene associated with neurofibromatosis
Describe mechanism of hormones that use Ca or phosphatidylinostides (or both)
- hormone binds to 7 TM serpentine
- Receptor activates a G-protein by GTP exchange
- activated alpha-subunit activates PLC
- Two second messengers are produced
5/ Protein Kinase C is activated
