Hormone Signaling Pathways Flashcards
(29 cards)
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
