Hormone Signaling Pathways Flashcards
General Features of Hormones
LO1
- 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
Hormone signaling step process
- Biosynthesis
- Storage
- Secretion
- Transport to target tissue/ cells
- Recognition and binding to receptors
- Activation of signal transduction pathway (on switch)
- Amplification and relay of signal
- Cellular response
- Degradation (off switch)
Ligand
receptor complex that activate or inhibit cellular pathways=> elicit cellular response
signal terminated by removal by signaling or receptor or inactivation of signaling events
Signaling Mechanisms used by hormones
LO2
- Endocrine- molecule released by cell distant from target cell and transported via bloodstream to target cell
exm. epinephrine - Paracrine- molecule released by one cell type and diffuses to a neighboring target cell of a different cell type
exm. testosterone - Autocrine- molecule acts on same cell type as secreting cells themselves
exm. interleukin-1 - Juxtacrine signaling- molecule stays attached to secreting cell and binds to a receptor on an adjacent target cell
exm. heparin-binding epidermal growth factor
List water soluble hormones
aka hydrophilic
- epinephrine
- insulin
- glucagon
- growth hormone
List lipid soluble hormones
aka hydrophobic
- estrogen
- testosterone
- cortisol
- 1,25 dihydroxy cholecalciferol
Hydrophilic Hormone Signaling
- describe
- hormones
- receptors
LO3
- 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)
Lipophilic Hormone Signaling
- describe
- hormone
- receptors
LO3
- 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
Hydrophilic medications
- describe
- exm
LO3
have short half lives (seconds to minutes)
exm
- epinephrine: to treat severe acute allergic reaction
- insulin- shot given right before eating
Lipophilic medications
- describe
- exm
LO3
have long half lives (hours to days)
exm. oral contraceptives
- contain ethinyl estradiol
Hydrophilic hormone signaling via G protein coupled receptors
LO4
- 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
Four variations in GPCR signaling
- Gs- stimulates adenylate cylase
- Gi- inhibit adenylate cyclase
- Gt- stimulates cGMP phosphodiesterase
- Gq- activates phospholipase C
Hydrophilic hormone signaling via Receptor Tyrosine Kinase receptors
LO4
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)
Structures of Insulin
- primary
- secondary and tertiary
- active and inactive form
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
Basic Insulin Synthesis and Secretion
- 10 steps
LO5
- preproinsulin mRNA
- translated into preproinsulin protein
- Translocated in ER lumen
- Cleaved by protease to form proinsulin
- Folded and transported to Golgi
- Packaged into immature granules
- Cleaved by proteased to form insulin and C peptide
- Immature granules become mature granules
- Contain hexameric crystallized insulin (3 dimers)
- Insulin and C peptide released together
Regulation of Insulin Synthesis and Secretion
- phases
LO5
- Rapid but transient phase
- readily releasable pool (RRP)
- limited pool of granules (5%) - Sustained phase
- Reserve pool (95%)
- granules must undergo mobilization before they gain release competence
RAS-dependent insulin signaling
-steps (6)
LO5
- Insulin bind to insulin receptor aRTK
- autophosphorylation of tyrosine residue B subunit
- residue bind to insulin receptor substrate 1 (IRS1)
- IRS 1 phosphorylates on tryosine by insulin receptor
- IRS1 + GRB2=> activationof RAS and MAP kinase pathway
- increase transcription of glucokinase=> begins glycolysis
RAS-independent insulin signaling
- steps (9)
LO5
- insulin binds to RTK
- autophosphorylation of tyrosine residue
- phosphotyrosine + IRS1
- IRS1 phosphorylates tyrosine by insulin receptor
- IRS1 recruits PI3 kinase
- PI3 kinase=> PIP2 +PIP3
- stimulate recruitment of PKB
- active PKB => AKT phosphorylate
- stimulate glucose uptake and storage
- inhibit GSK3
- activate GLUT4 from cytoplasm to plasma membrane
Termination of Insulin Signaling
LO5
- internalized by exocytosis
- degraded by protease or recycled back to plasma membrane
Insulin Resistance
-reasons
LO5
- amount of glucose cleared from blood in response to fixed dose of insulin
- downregulation of insulin receptor (mutation)
- defect in insulin signaling
- . defect in IRS1 and IRS2
- 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 - reduced activation of PKB
Nuclear Receptors
LO6
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
Orphan Receptors
ligand unknown
-receptors discovered by DNA sequencing
retinoids,thryoid hormones, vitamin D, xenobiotics, androstane
Molecular Structure of Nuclear Receptors
- domain
- steps
LO6
Domains
- ligand binding domain
- activation function 1 domain
- DNA binding domain
- LBD bind to molecule=> regulate ligand-dependent activation of receptor => conformational change
- AF1 independent of ligand binding => modify conformation of entire receptor
- DBD bind to hormone response element (HRE) => upstream signaling
- exists as homo or heterodimer
Estrogen Receptors
LO7
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
Era mostly expressed in …
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
ERB mostly expressed in…
ovaries, prostate, with lower expression in lung, brain, bone, and vasculature
Molecular mechanism of Nuclear estrogen receptor: genomic pathway
- 3 steps
LO7
Genomic Effect
- Estrogen receptor (nucleus) bind to ligand => conformational change => dimerization with ERE sequence in DNA
- ER-DNA complex recruits coactivators => modify chromatin structure via Histone acetyl transferase activity (HAT)
- activates transcription
Tamoxifen
- 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
estrogen receptor: non-genomic pathway
LO7
- 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
