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Endo Repro Midterm > Hormone Signaling Pathways > Flashcards

Hormone Signaling Pathways Flashcards

1
Q

General Features of Hormones

LO1

A
  • messenger molecules
  • synthesized and secreted by specialized cells (endocrine cells)
  • released into blood stream
  • bind to specific receptors
  • activation of signal transduction and/or alteration in gene expression=> cell type specific response
  • amplification of signla
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2
Q

Hormone signaling step process

A
  1. Biosynthesis
  2. Storage
  3. Secretion
  4. Transport to target tissue/ cells
  5. Recognition and binding to receptors
  6. Activation of signal transduction pathway (on switch)
  7. Amplification and relay of signal
  8. Cellular response
  9. Degradation (off switch)
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3
Q

Ligand

A

receptor complex that activate or inhibit cellular pathways=> elicit cellular response

signal terminated by removal by signaling or receptor or inactivation of signaling events

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4
Q

Signaling Mechanisms used by hormones

LO2

A
  1. Endocrine- molecule released by cell distant from target cell and transported via bloodstream to target cell
    exm. epinephrine
  2. Paracrine- molecule released by one cell type and diffuses to a neighboring target cell of a different cell type
    exm. testosterone
  3. Autocrine- molecule acts on same cell type as secreting cells themselves
    exm. interleukin-1
  4. Juxtacrine signaling- molecule stays attached to secreting cell and binds to a receptor on an adjacent target cell
    exm. heparin-binding epidermal growth factor
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5
Q

List water soluble hormones

A

aka hydrophilic

  • epinephrine
  • insulin
  • glucagon
  • growth hormone
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6
Q

List lipid soluble hormones

A

aka hydrophobic

  • estrogen
  • testosterone
  • cortisol
  • 1,25 dihydroxy cholecalciferol
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7
Q

Hydrophilic Hormone Signaling

  • describe
  • hormones
  • receptors

LO3

A
  • cannot penetrate plasma membrane
  • interact with specific receptors at cell surface

Exm

  • epinephrine
  • insulin
  • glucagon

signaling molecule- receptor complex intitates productions of second messenger molecule inside cell=> cellular response

Receptors (on plasma membrane)

  • G protein-coupled receptors (GPCR)
  • receptor tyrosine Kinase (RTK)
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8
Q

Lipophilic Hormone Signaling

  • describe
  • hormone
  • receptors

LO3

A
  • passively diffuse through plasma of target cell
  • hormone (ligand) binds to specific receptor proteins inside cells
  • hormone-receptor complex acts as a transcription factor

exm

  • steroid hormones
  • cortisol
  • 1,25 dihydroxy cholecalciferol

Receptors

  • Cytoplasmic receptors
    • inactive complex with HSp90=> hormone response eleemnt (HRE)
  • nuclear receptors- nucleus bound to DNA
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9
Q

Hydrophilic medications

  • describe
  • exm

LO3

A

have short half lives (seconds to minutes)

exm

  • epinephrine: to treat severe acute allergic reaction
  • insulin- shot given right before eating
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10
Q

Lipophilic medications

  • describe
  • exm

LO3

A

have long half lives (hours to days)

exm. oral contraceptives
- contain ethinyl estradiol

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11
Q

Hydrophilic hormone signaling via G protein coupled receptors

LO4

A
  • trimeric G proteins- 3 subunits

inactive G protein -> GDP to GTP-> activate via GEF-> alpha subunit separates from beta and gamma subunits (activate via GEF)

inactivate via intrinsic GTPase activity via GAP

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12
Q

Four variations in GPCR signaling

A
  1. Gs- stimulates adenylate cylase
  2. Gi- inhibit adenylate cyclase
  3. Gt- stimulates cGMP phosphodiesterase
  4. Gq- activates phospholipase C
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13
Q

Hydrophilic hormone signaling via Receptor Tyrosine Kinase receptors

LO4

A

component:

  • EC domain
  • alpha-helical transmembrane domain
  • IC domain with TK activity

Binding of ligand=> dimerization => phosphorylates tyrosine=> recognized by adaptor and docking proteins => activate downstream signaling (RAS dependent (MAPK)or RAS independent) => phosphorylation in gene transcription and protein activity

Signal terminates via multiple mechanism (ex. protease, RAS inactivation, dephosphorylation)

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14
Q

Structures of Insulin

  • primary
  • secondary and tertiary
  • active and inactive form
A

Primary Structure

  • two peptide chains (A chain and B chain)
  • linked by disulfide bridges

a chain= 21 AA
b chain = 30 AA

Secondary and Tertiary Structure

  • 6 insulin molecules= hexamer
  • 3 fold symmetry in Zinc center

Inactive insulin= hexamer
Active insulin= monomer

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15
Q

Basic Insulin Synthesis and Secretion
- 10 steps

LO5

A
  1. preproinsulin mRNA
  2. translated into preproinsulin protein
  3. Translocated in ER lumen
  4. Cleaved by protease to form proinsulin
  5. Folded and transported to Golgi
  6. Packaged into immature granules
  7. Cleaved by proteased to form insulin and C peptide
  8. Immature granules become mature granules
  9. Contain hexameric crystallized insulin (3 dimers)
  10. Insulin and C peptide released together
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16
Q

Regulation of Insulin Synthesis and Secretion
- phases

LO5

A
  1. Rapid but transient phase
    - readily releasable pool (RRP)
    - limited pool of granules (5%)
  2. Sustained phase
    - Reserve pool (95%)
    - granules must undergo mobilization before they gain release competence
17
Q

RAS-dependent insulin signaling
-steps (6)

LO5

A
  1. Insulin bind to insulin receptor aRTK
  2. autophosphorylation of tyrosine residue B subunit
  3. residue bind to insulin receptor substrate 1 (IRS1)
  4. IRS 1 phosphorylates on tryosine by insulin receptor
  5. IRS1 + GRB2=> activationof RAS and MAP kinase pathway
  6. increase transcription of glucokinase=> begins glycolysis
18
Q

RAS-independent insulin signaling
- steps (9)

LO5

A
  1. insulin binds to RTK
  2. autophosphorylation of tyrosine residue
  3. phosphotyrosine + IRS1
  4. IRS1 phosphorylates tyrosine by insulin receptor
  5. IRS1 recruits PI3 kinase
  6. PI3 kinase=> PIP2 +PIP3
  7. stimulate recruitment of PKB
  8. active PKB => AKT phosphorylate
  9. stimulate glucose uptake and storage
    - inhibit GSK3
    - activate GLUT4 from cytoplasm to plasma membrane
19
Q

Termination of Insulin Signaling

LO5

A
  • internalized by exocytosis

- degraded by protease or recycled back to plasma membrane

20
Q

Insulin Resistance
-reasons

LO5

A
  • amount of glucose cleared from blood in response to fixed dose of insulin
  1. downregulation of insulin receptor (mutation)
  2. defect in insulin signaling
  3. . defect in IRS1 and IRS2
  4. phosphorylation of serine instead of tyrosine in IR and IRS
    - ser/thr kinase inactivates IRS 1 and 2=> degradation
    - ser/thr kinase activated by cytokine, FFA, DAG, ceramide
  5. reduced activation of PKB
21
Q

Nuclear Receptors

LO6

A

ligands for lipophilic hormones
-located in nucleus or cytosol=> translocation to nucleus=> influence gene expression

glucocorticoids, mineralcorticoids, estrogen, progesterone, androgens

important drug target
- serve as BOTH effector and receptors for signal

22
Q

Orphan Receptors

A

ligand unknown
-receptors discovered by DNA sequencing

retinoids,thryoid hormones, vitamin D, xenobiotics, androstane

23
Q

Molecular Structure of Nuclear Receptors
- domain
- steps
LO6

A

Domains

  • ligand binding domain
  • activation function 1 domain
  • DNA binding domain
  1. LBD bind to molecule=> regulate ligand-dependent activation of receptor => conformational change
  2. AF1 independent of ligand binding => modify conformation of entire receptor
  3. DBD bind to hormone response element (HRE) => upstream signaling
  • exists as homo or heterodimer
24
Q

Estrogen Receptors

LO7

A

Two major types= ERa and ERb

both are estrogen-dependent transcription factors

  • influence multiple target genes
  • mediate variety of biological effects
  • ERB can substitute for ERa in some biological pathways
  • dimerize to form either homodimers or heterodimers
25
Q

Era mostly expressed in …

A

Female reproductive tract

  • uterus, vagina, ovaries, mammary gland, hypothalamus, endothelial cells, vascular smooth muscle
  • both era and erb in breast cancer but ERa predominant form responsible for growth regulation
26
Q

ERB mostly expressed in…

A

ovaries, prostate, with lower expression in lung, brain, bone, and vasculature

27
Q

Molecular mechanism of Nuclear estrogen receptor: genomic pathway
- 3 steps

LO7

A

Genomic Effect

  1. Estrogen receptor (nucleus) bind to ligand => conformational change => dimerization with ERE sequence in DNA
  2. ER-DNA complex recruits coactivators => modify chromatin structure via Histone acetyl transferase activity (HAT)
  3. activates transcription
28
Q

Tamoxifen

A
  • antagonist of ER
    1. binding of tamoxifen to estrogen receptors produce different receptor conformation
    2. recruits different set of proteins (co-repressors)
  • histone deacetylase (HDAC1) prevent interaction with GTA => preventing transcription
29
Q

estrogen receptor: non-genomic pathway

LO7

A
  • some ER in plasma membrane
    • cholesterol enriched microdomain (caveolae)
  • belong to GPCR and RTK type of receptors
  • effects mediated through metabolic changes and gene expression

Endo Repro Midterm (12 decks)

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