Intro to Hormones - Dr. Magat FINAL

Introduction to Hormones –Part IDra. Magat January 4, 2010

Let us first define SIGNAL TRANSDUCTION

Signal transduction – a process in cells whereinformation is converted into a cellular response

- the information to be converted comes in theform of signals which could be chemical orphysical (glucose concentration, light, temperature changes, etc.)

Features of Signal Transduction [Lehninger] Specificity

o precise molecular complementarity between signal and receptor, mediated by the same kinds of weak (non covalent) forces that enzyme-substrate and antigen-antibody interactions.

o Specificity is further achieved by the presence of receptors in certain cell types only

Amplification by enzyme cascadeo enzyme associated with a signal receptor

is activated and in turn catalyzes activation of many molecules of a 2nd

enzyme, each of which activates many molecules of a 3rd enzyme and so on

Desensitizationo When a receptor is activated, it triggers a

feedback circuit that shuts off itself (the receptor), or removes it from the cell surface

o This occurs so that the sensitivity of the receptor is modified

o when a signal is present continuously, the receptor is desensitized; when signal falls below a certain threshold, the system again becomes sensitive

Integrationo the ability of the system to receive

multiple signals and produce a unified response appropriate to the needs of the cell or organism; different signalling pathways converse at several levels generating wealth of interactions that maintain homeostasis

Key Steps in Signal Transduction

1. Release of primary messenger (neurotransmitters, hormones)

2. Reception of primary messenger (signal receptor concept)

3. Delivery of message inside cell by second messengers (or in some cases by the hormone itself)

4. Activation of effectors alter physiologic response (effect on the target cells)

5. Termination of signal (there is regeneration of the receptor)

1 of 8 Page

Hormones - Chemical signals /substances that are synthesized and secreted from endocrine glands directly into the circulation (bloodstream) to elicit specific responses from one or more target tissues

Hormones can be classified according to:- Chemical composition- Solubility properties- Location of receptors- Nature of signal used to mediate hormonal action

within a cell

Based on structure/chemical compositionStructure HormonesPolypeptides Hypothalamus

PituitaryThyroid: CalcitoninParathyroidAlimentary tractHeart: atrial natriuretic peptideGonads: inhibinPlacenta: choriogonadotropin, placental lactogen, relaxinLiver: angiotensinEpo

Steroids Adrenal cortex: glucocorticoids (cortisol, corticosterone), mineralocorticoids (aldosterone)Gonads: estrogen, estradiol, estrone, progestins, androgensPlacenta: estrogens, progestinsKidney: 1,25-dihydroxycholecalciferol

Amino acid derivatives Thyroid: T3, T4Adrenal medulla: epinephrine, norepinephrine

Solubility properties:

Lipophilic/ Hydrophobic – able to traverse cell membrane

Lipophobic/ Hydrophilic

Location of the receptor:

Intracellular - the receptor is found inside the cytoplasm or the nucleus (e.g. thyroid and steroid hormones)

Plasma membrane – receptor resides in the plasma membrane as an embedded membrane protein (e.g. proteins, peptides, catecholamines)

Nature of signal used to mediate hormone action within the cell:

a. Hormones that bind to intracellular receptors Include the steroid and thyroid hormones

(androgens, calcitriol, estrogens, glucocorticoids, mineralocorticoids, progsetins, retinoid acid, T3 and T4)

Lipophilic – can easily traverse the plasma membrane

Derived from cholesterol (except T3 and T4 which are amino acid derivatives)

Utilize transport proteins in the blood (e.g. transcortin for corticoids, androgen-binding globulin, sex hormone-binding protein, thyroid-binding globulin and thyroid-binding prealbualbumin)

The relative percentage of the bound and free hormone is determined by the binding affinity and binding capacity of the transport protein

The free form (active hormone) finds the receptor of the target cell at the cytosol or nucleus.

b. Hormones that bind to cell surface receptors Hydrophilic Do not enter the target cell First messengers Initiate receptors in the plasma membranes Produce 2nd messengers when they bind to

their receptors in the presence of stimulatory or mediator proteins

Act through signal transduction where 2nd

messengers are used to trigger a series of molecular interactions that alter the physiologic state of the cell

2nd messengers used include cAMP, cGMP, Calcium or PIP2 and kinase or phosphatase cascade)

Classification of hormones based on mechanism of action [Harper]

General features of hormone classes.Class I Class II

Types Steroids, iodothyronines, calcitriol, retinoids

Polypeptides, proteins, glycoproteins, cetacholamines

Solubility Lipophilic / hydrophobic

Hydrophilic

Trasnport proteins

YesSteroid hormones: transcortin, androgen-binding protein, albuminThyroid hormones: thyroid-binding globulin, thyroid-binding prealbumin

No

Plasma halflife Long (hours to days)

Short (minutes)

Receptor Intracellular-located in the cytoplasm or nucleus of the target cell

Plasma membrane / cell surface

Mediator Receptor-hormone complex

cAMP,cGMP,Ca2+, metabolites of complex phosphoinositols, kinase cascades

I. Hormones that bind to intracellular receptors: Androgens Calcitriol (1,25[OH]2-D3) Estrogens Glucocorticoids Mineralocorticoids Progestins Retinoic acid Thyroid hormones (T3, T4)

II. Hormones that bind to cell surface receptors:A. 2nd messenger is cAMPB. 2nd messenger is cGMPC. 2nd messenger is CalciumD. 2nd messenger is a kinase or phosphatase

cascade

2 of 8 |PageCreated by: Hwang- Javier Edited by: Constantino

What again are second messengers?They are INTRACELLULAR signalling

molecules which activate and recruit enzymes for further signal transduction

They:- may be rapidly formed from precursors by enzymatic reactions-may be released from intracellular stores- may be rapidly inactivated or stored in specific compartments- may activate different effector proteins- allow amplification of signals

A. 2nd messenger is cAMPcAMP- formed from ATP by adenylyl cyclase

adenylyl cyclase- found on cell membrane and is activated by g-proteins

Hormones which bind to cell membrane receptors and use cAMP as a 2nd messenger:

α-2 adrenergic cathecolamines β- adrenergic cathecholamines adrenocorticotropic hormone (ACTH) angiotensin II antidiuretic hormone (ADH) Calcitonin Human chorionic gonadotropin (HCG) Corticotropin releasing hormone (CRH) Dopamine Epinephrine Histamine (H2) Serotonin Odorants Tastants Follicle-stimulating hormone (FSH) Glucagon Lipotropin (LPH) Luteinizing hormone (LH) Melanocyte-stimulating hormone (MSH) Parathyroid hormone (PTH) Somatostatin Thyroid-stimulating hormone (TSH)

B. 2nd messenger is cGMPcGMP- formed by catalysis via guanylyl cyclase from GTP

Hormones which bind to cell membrane receptors and use cGMP as a 2nd messenger

Atrial natriuretic factor (ANF) Nitric oxide (NO)

C. 2nd messenger is Ca2+ / phosphatidylinositols

Acetylcholine (muscarinic) α2-adrenergic cathecholamines Angiotensin II ADH Cholecystokinin Gastrin Ginadotropin releasing hormone (GnRH) Oxytocin Platelet-derived growth factor (PDGF) Substance P Thyrotropin-releasing hormone (TRH) Angiogenin ATP Auxin Gastrin releasing peptide Glutamate

GRH Histamine (H1) Serotonin Vasopressin

D. The 2nd messenger is a kinase / a phosphatase cascade

Chorionic somatomammotropin (CS) Epidermal growth factor (EGF) Erythropoeitin Fibroblast growth factor (FGF) Growth hormone Insulin; insulin-like growth factors (IGF-1,

IGF-2) Prolactin Nerve growth factor Platelet-derived growth factor (PDGF)

MOA: Signal Transduction

1. G-protein coupled receptor (GPCR) -transmembrane receptor

2. Receptor tyrosine kinase (RTKs) - there is extracellular and intracellular domain

Extracellular – ligand binding site close to amino terminalIntracellular – carboxyl end

3. Receptor guanylyl cyclase

4. Gated ion channel

5. Adhesion receptor

6. Steroid receptor

Discussion on mode of action of receptors are discussed below with an example of a signal transduction pathway which uses the receptor.

I. G protein coupled receptor [Lehninger]


G protein

- stimulatory protein which will in turn stimulate production of adenylate cyclase

- exists as a trimer α,β,γ - α is the biggest unit

3 essential components that define signal trandusction through GPCRs:

1. 7 transmembrane helical segmentsstructure: 7 helices, 20-22 Amino acids, a carboxyl end, 3 extracellular Amino acids, 3 intra cellular amino acids

2. An effector enzyme in the plasma membrane that generates a 2nd msgr

3. Guanosine nucleotide-binding protein (G-protein) that activates the effector enzyme

Mechanism of Action: (active: GTP, inactive: GDP)1. Initially the G-protein α subunit is bound to GDP

(inactive state) and β and γ subunits are complexed together.

2. On hormone binding, the activated receptor interacts with the αβγ heterotrimer to promote conformational change. GDP is released and GTP is now bound.

3. The GTP-GDP exchange stimulates dissociation of the complex from the receptor.

4. The α-subunit-GTP complex then moves to and binds to a nearby membrane effector molecule, such as the enzymes adenylyl cyclase, guanylyl cyclase, phospholipase C or to an ion channel carrier protein.

Summary: upon binding GPCRs catalyze the exchange of GTP for GDP on the G proteindissociation of Gα subunit Gα then stimulates or inhibits activity of an effector enzyme changing the level of its second-messenger product.

β-adrenergic receptor Muscle, liver, adipose tissue An integral protein with 7 hydrohpobic regions of

20 to 28 amino acid residues Activates a stimulatory G protein, Gs, thereby

activating Adenylyl cyclase and raising the concentration of 2nd msgr cAMP.

cAMP stimulates cAMP-dependent protein kinase to phosphorylate key target enzymes, changing their activities.

[cAMP] is eventually reduced by cAMP phosphodiesterase, and Gs turns itself off by hydrolysis of GTP to GDP, acting as a self-limiting binary switch.

When signal persists, β-adrenergic receptor and β-arrestin temporarily desensitize the receptor and cause it to move into intracellular vesicles.

β-adrenergic pathway: [Lehninger]1. Epinephrine binds to its specific receptor2. The occupied receptor causes replacement of the GDP bound to Gs by GTP, activating Gs

-Gs is activated when its nucleotide-binding site is occupied by GTP while inactivated if occupied by GDP

3. Gs (α-subunit) moves to adenylyl cyclase and activates it

-Gsα is self-limiting;4. Adenylyl cyclase catalyzes the formation of cAMP5. cAMP activates PKA

-PKA catalyzes the phosphorylation of inactive phosphorylase b kinase to yield active form

6. Phosphorylation of cellular proteins by PKA causes the cellular response to epinephrine

7. cAMP is degraded by cyclic nucleotide phosphodiesterase to 5’-AMP, reversing the activation of PKA

Desensitization of β-adrenergic receptors-occurs when the signal (epinephrine) persists

1. Binding of Epinephrine to β-adrenergic receptor triggers dissociation of GSβγ and GSα

2. GSβγ recruits βARK to the membrane, where it phosphorylates Ser residues at the carboxyl terminus of the receptor3. βarr binds to the phosphorylated carboxyl-terminal domain of the receptor

-the binding of βarr prevents interaction between the receptor and the G protein as well as the removal of receptors from the PM by endocytosis into small intracellular vesicles

4. Receptor-arrestin complex enters the cell by endocytosis5. In endocytic vesicle, arrestin dissociates; receptor is dephosphorylated and returned to cell surface

Activation of G-protein:GDP (heterotrimeric) -----GEF ----> GTPGEF – guanosine nucleotide exchange factor for activation of guanosine phosphoryl grpGTP – largest subunit; convert itself to inactive formRas protein – where GTP is located; prevent inappropriate activation of GDP to GTP


Ras Protein – small G-proteins The Ras protein has switch 1 and switch 2

regions. In GTP-bound conformation, the G protein exposes these previously buried regions that interact with proteins downstream in the signaling pathway, until the G protein inactivates itself by hydrolyzing GTP to GDP.

Thus there is a loss of hydrogen bonds to Threonine, Thr35 (switch 1) and glycine, Gly60 (switch 2) regions.

Alanine, Ala146 hydrogen bonds to the guanine oxygen allowing GTP, but not ATP, to bind.

Once there is hydrolysis, there is a release of switch regions (relaxed/inactive form)

Clinical CorrelationVibrio Cholera

-gram negative choliform-causes severe dehydration and diarrhea-transmitted through feco-oral route

Cholera toxin secreted by Vibrio cholera is a heterodimeric protein

o Subunit B: binds to specific gangliosides on surface of intestinal epithelial cells and provides route for subunit A to enter cells

o Subunit α: broken into A1 and A2 fragment after entering cell

A1 associates with ARF6 (a G protein) through residues in its switch I and II regions – accessible when ARF6 is bound to GTP (active form)

A1 is thus activated, catalyzing the transfer of ADP-ribose from NAD+ to critical Arg residue in P loop of α subunit of Gs rendering Gs permanently active

permanent activation of Gs results in continuous activation of adenylyl cyclase of intestinal epithelial cells chronically high concentration of cAMP chronically active *PKA PKA phosphorylates CFTR Cl- channels and Na+ H+ exchanger in intestinal epithelial cells results to efflux of NaCl trigger massive H2O loss through intestine due to osmotic imbalance result to dehydration and loss of electrolytes

Summary: cholera toxin permanent activation of G protein excessive activation of AC chronic elevation of cAMP severe dehydration

*Activation of PKA:PKA in its inactive form has 4 subunints- 2 regulatory- 2 catalytic The subunits are held together by AKAP (A kinase anchor protein)- cAMP binds to the 2 regulatory subunits- the release of the regulatory subunits will activate the enzyme.

MOA of PIP2 2nd messenger systemGTP will activate PLC--- PLC Hydrolyzes PIP2 and will become DAG and IP3----- IP3 will activate the release of Ca 2+ in SER------ Ca 2+ will then activate PKC (membrane bound) along with DAG (PKC will undergo phosphorylation)

Phospholipase C Specific for PIP2

Produces 2 potent 2nd messengerso DAG – DAG and calcium act together to

activate PKCo IP3 – water soluble compound; diffuses to

ER binds to calcium channels, opens them elevated Ca activates PKC .

Calcium When intracellular calcium increasescalmodulin

binds calcium conformational change activates CaM Kinase phosphorylates target enzymesNote: Calmodulin is an integral sububit of CaM kinase.

Calcium triggers ATP-requiring muscle contractions while activating glycogen breakdown, providing fuel for ATP synthesis.Note: Calmodulin is a regulatory subunit of phosphorylase b kinase of muscles.

In some tissues, both enzymes that produce cAMP (AC) and degrades it (phosphodiesterase) are stimulated by calcium.

II. Receptor Tyrosine Kinases (RTKs) [Lehninger]-plasma membrane receptors with intrinsic protein kinase activity-plasma membrane receptors that are also enzymes (have a ligand-binding domain on the extracellular face of the plasma membrane and an enzyme active site on the cytoplasmic face/-when one of these receptors is activated by its extracellular ligand, it catalyzes the phosphorylation of several cystosolic or plasma membrane proteins.Ex. Insulin receptor Epidermal growth factor (EGF-R)

JAK-STAT SIGNALING SYSTEM-a variation of RTK having no intrinsic protein kinase activity but, when occupied by their ligand, bind a cytsolic Tyr kinase.-regulates the formation of erythrocytes in mammals-cytokine: Erythropoietin (EPO)

Binding of EPO causes dimerization of EPO receptor↓

Dimer bind and activate JAK (Janus kinase)↓

Activated JAK phosphorylates several Tyr residues.

(a.)One signaling pathway SH2 domain in STAT5 binds P –Tyr residue in

EPO receptor , bringing it in proximity with JAK JAK phosphorylates STAT Phosphorylated STAT forms dimers, thus

exposing a nuclear localization system (NLS) Dimerization and exposure of NLS translocation

of STAT into the nucleus In nucleus, STAT5 turns on expression of EPO

controlled genes growth enhancing mechanism of EPO esp. on RBC

(b.)Second signaling pathway After , EPO binding and autophosphorylation of

JAK, Grb2 binds P –Tyr in JAK5 of 8 |Page

Created by: Hwang- Javier Edited by: Constantino

This triggers the MAPK cascade, as in the insulin system.

III. Receptor Guanylyl cyclases [Lehninger]-plasma membrane receptors with an enzymatic cytoplasmic domain-ligand binding to extracellular domain stimulates conversion of GTP to intracellular 2nd messenger : guanosine 3’,5’-cyclic monophosphate (cGMP) cGMP-activates cytosolic protein kinase (PKG) that phosphorylates cellular proteins and thereby changes their activities-carries different messages in different tissues

Kidney and Instestine: ion transport and water retentionCardiac muscle: relaxationBrain: development and brain function

Atrial natriuretic factor (ANF)-released by cardiac cells in the atrium when increased blood volume stretches the atrium-carried in the blood to the kidney, it activates guanylyl cyclase in the cells of the collecting ducts

Clinical correlation:

Atriopeptins (ex. atrial natriuretic factor)

↓Bind & activate guanylyl cyclase

↓cGMP 50X

↓Natriuresis, diuresis, vasodilation & inhibition of aldosterone secretion

Nitric Oxide Nitroglyceron tablet

↓Converted to NO

↓Activates guanylyl cyclase

↓cGMP synthesis

↓relaxation of smooth muscle cells in the blood vessels

↓vasodilation

↓improved O2 delivery to the heart

↓relief from angina pain

Viagra (Sildenafil)↓

Inhibits cGMP phosphodiesterase /cGMP specific phosphodiesterase type 5 (PDE5)

↓Inhibits cGMP (corpus cavernosum)

↓Muscle relaxation and vasodilation

↓Sustained erection

**there should be sexual stimulation to activate the NO/ cGMP system, otherwise the erection would not proceed

Note: NO is a short-lived messenger that stimulates soluble guanylyl cyclise, raising [cGMP] and stimulates PKG.

IV. Gated Ion Channel [Lehninger]

Ion channels underlie electrical signaling in excitable cells (sensory cells, neurons, and myocytes)

Signal transducers that provide a regulated path for the movement of inorganic ions such as Na+, K+, Ca2+ and Cl- across the plasma membrane in response to stimuli.

Activated by binding to its specific ligand or by a change in the transmembrane electrical potential.

Usually very selective to one or more ions Open in response to specific ligand molecules

binding to the extacellular domain of the receptor protein.

Voltage-gated ion channels produce neuronal action potentials.

o Voltage-Gated Na+ Channels-> closed when membrane is at rest but briefly open when membrane is depolarized.

o Voltage-Gated K+ Channels-> open in response to depolarizing flow of Na+

(influx) thus rapidly countered by repolarizing flow of K+ out (efflux)

o Voltage-Gated Ca2+ Channels-> open due to the wave of depolarization and repolarization caused by the activity of Na+and K+ channels thus triggering the release of the neurotransmitter acetylcholine.

Nicotinic Acetylcholine Receptor Mediates the passage of an electrical signal at

synapses and at a neuromuscular junction. Has an intrinsic timing mechanisms that closes

the gate milliseconds later. Has 5 subunits

o single copies of β, γ, and δo 2 identical α subunits that each contain

an acetylcholine-binding site-> when acetylcholine binds , allosteric conformational change include twisting of the M2 helices is induced

o Each has 4 transmembrane helical segments (M1 to M4)

o Surround a central pore which is lined with their m2 helices

o Near the center of the bilayer ring of bulky hydrophobic side chains of Leu residues in the M2 helices-> prevents the passage of ions->allosteric conformational change draws these hydrophobic side chains away from the center of the channel->opening the passage of ions

V. Adhesion Receptor or Cell Adhesion Molecules (CAM)


Located on the cell surface involved with binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion.

Typically transmembrane receptors and are composed of three domains:

o An Intercellular domain that interacts with the cytoskeleton

o A transmembrane domain and an extracellular domain that interacts either with other CAMs of the same kind (homophilic binding)

o With other CAMs or the extracellular matrix (heterophilic binding)

Immunoglobulin Superfamily CAMs (IgSF CAMs) Bing integrins or other different IgSF CAMs (either

homophilic or heterophilic)o NCAMs-> Neural Cell Adhesion

Molecules (neural patterning)o ICAM1 -> Intercellular Cell Adhesion

Moleculeo VCAM1 -> Vascular Cell Adhesion

Moleculeo PECAM1 -> Platelet-endothelial Cell

Adhesion Molecule -> role in immune response and inflammation

Has an extracellular domain, which contains several Ig-like intrachain disulfide-bonded loops with conserved crysteine residues, a transmembrane domain, and an intracellular domain that interacts with the cytoskeleton.

Integrins Heterophilic or bind IgSF CAMs or the ECM Heterodimers, consisting in two non-covalently

linked subunits, called alpha and beta. 24 different alpha subunit are known that can link in many different combinations with the 9 different beta subunits.

Cadherins Homophilic, Ca2+-dependent (when calcium is

bound, the extracellular domain has a rigid, rod-like structure)

Most important members of this family are E-cadherins (epithelial), P-cadherins(placental) and N-cadherins

Involved in embryonic development and tissue organization

Selectins Heterophilic CAMs that bind fucosylated

carbohydrates, mucins; Ca2+ - dependent Three family members are E-selectin

(endothelial), L-selectin (leukocyte) and P-selectin (platelet)

VI. Steroid Receptor

Steroid Hormone Receptor The unliganded glucocorticoid receptor and the

aldosterone receptor reside in the cytoplasm, while others are in the nucleus.

Intracellular receptors that initiate signal transduction for steroid hormones.

Steroid Hormone Lipid-soluble, readily pass through the plasma

membranes into the cytosol of target cells. Combine with specific intracellular receptors, the

hormone-receptor complex act in the nucleus, causing genes to be expressed.

Most steroid hormone receptors are localized in the nucleus while others may move from the cytosol to the nucleus only when bound to the hormone.

Major steroid hormones: adrenocortical hormones, sex hormones (androgens and estrogens) and vitamin D-derived hormones.

Mechanism of Action:1. Dissociation of free hormone from circulating

transport. o Steroid hormone dissociates from a

plasma transport protein2. Diffusion of free ligand into cytosol or nucleus

o Free steroid enters the cell by diffusion through the lipid bilayer

o The unliganded receptor (Glucocorticoid receptor) contains heat shock protein or hsp, which masks the receptor DNA-binding domain.

3. Binding of ligand to cytoplasmic or nuclear receptor

o Causes conformational change -> “activation”

o Rrelease of the associated proteins, including the dimer of Hsp

4. Activation of cytosolic or nuclear hormone-receptor complex to DNA-binding form

o Exposure of positively charged amino acid residues located within the DNA-binding domain

5. Translocation of activated cytosolic hormone-receptor complex into nucleus

o The ligand-receptor complex translocates to the nucleus

o binds to DNA as homodimero searches the DNA for specific, high-

affinity acceptor sites6. Binding of activated hormone-receptor complexes

to specific hormone response elements (HREs) within the DNA

o Regulator of gene transcription7. Synthesis of new proteins encoded by hormone-

responsive geneso New mRNAs are translocated to the

cytoplasmo Translation complexes for the synthesis of

proteins8. Alteration in phenotype or metabolic activity of

target cell mediated by specifically induced proteins.

The NF-kB Pathway regulated by GC [Harper]


NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)

- It is a protein complex that controls transcription of DNA

- Active NF-κB turns on the expression of genes that keep the cell proliferating

- Thus if there is no inhibition on the NF-kB, cells will continuously divide and would lead to uncontrolled proliferation of cells, and eventually might lead to cancer.

- But it is active when the cell is exposed to stimuli such as stress, cytokines, free radicals, UV rays, viruses and bacteria

- It plays a key role in immune responses

Glucocorticoids (Gc)- exert anti-inflammatory effects by interfering with a key transcription factor, nuclear factor kappa B (NF- κB)

Unstimulated immune cells- -transcription factor NF-κB is retained in

the cytoplasm Transcription factor NF-κB

-heterodimeric complex composed of p50 and p65 subunits- normally kept in the cytoplasm and is transcriptionally inactive

IκB (inhibitor of NF-κB family) - maintains the inactive state of NF-κB- activated by extracellular stimuli such as proinflammatory cytokines, reactive oxygen species and mitogens to IKK, tumor necrosis factor- IκBα -> phosphorylation on serines 32 and 36- IκBβ

IKK (Ikβ kinase complex) - a heterohexameric structure consisting

of α, β and γ subunits- - phosphorylates Ikβ on 2 serine residues

-target Ikβ for ubiquitination and subsequent degradation by the proteasomes

Ikβ degradation- free NF-κB will translocate to the nucleus - NF-κB will bind to gene promoters and activate transcription- induce cytokines(mediators of inflammation) and genes involved in inflammatory response.

Transcriptional regulation of NF-κB is mediated by coactivators such as CREB binding protein (CBP)

GC (glucocortisoid hormones) -> treatment of inflammatory and immune diseases

- anti-inflammatory and immunomodulatory actions by inhibition of NF-kB

3 mechanisms of inhibition of NF-kB:1. Gc increase Ikβ mRNA thus increase in Ikβ

protein and more efficient sequestration of NF-κB in the cytoplasm

2. Gc receptor competes with NF-kβ for binding to coactivators

3. Gc receptor directly binds to p65 subunit of NF-κB and inhibits its activation

Pathogenesis: ADS Introduction

Role in Inflammation

Type RegulationIntracellular Location

Biosignalling Process

Location of Receptor

NF-kB ↑P65: P50 Ik:Ba or Bb cytoplasm Kinase (IKK) Cell Membrane

Gc

↓Exo / Endogenous

Heat shock proteins (GR) cytoplasm (GR) 1st messenger Cytoplasm or

nucleus


Intro to Hormones - Dr. Magat FINAL

Documents

Transcript of Intro to Hormones - Dr. Magat FINAL