Hormone Signaing Pathways Flashcards
Endocrine signaling
H released into bloodstream to travel a long distance to reach its target.
Paracrine signaling
H released to act on a neighboring cell.
Autocrine signaling
H acts on the same cell that secreted it.
Juxtacrine signaling
H stays attached to secreting cell and binds to a receptor on an adjacent target cell.
How do hydrophilic Hs signal?
Bind to receptor on CM and induce a second messenger system.
What receptors can hydrophilic Hs use?
GPCRs
RTKs
Lipophilic Hs signal how?
They cross the CM to act as a transcription factor.
What receptors do lipophilic Hs bind?
Cytoplasmic receptors
Nuclear receptors
What is the hormone response element (HRE)?
The DNA sequence that the hormone-receptor complex (from the cytoplasm) binds to in the nucleus.
What are nuclear receptors bound to?
DNA directly
What kind of half-lives do hydrophilic meds have?
Very short (sec to min). Given at time of need (ex: Epi).
What kind of half-life do lipophilic meds have?
Long half-life (hours to days). Can be taken daily (birth control).
Hoe does an inactive G protein become active? Which enzyme facilitates this?
It must exchange its GDP for GTP. GEF causes this transaction.
How does the active GTP become inactivated?
There is intrinsic GTPase activity that hydrolysis GTP back into GDP.
What is the function of GTPase-activating protein (GAP)?
It accelerates the activity of GTPase, causing an increase in the rate of hydrolysis of GTP to GDP.
What occurs with the alpha, beta and gamma subunits once GTP is active?
Beta and gamma subunits remain intact and dissociate, leaving alpha attached to GTP.
How does the Gs pathway function?
What stops the cascade?
GTP activates AC —> cAMP —> active PKA —> phosphorylates target.
CAMP is acted on by PDE.
How does the Gi pathway work?
GTP inhibits AC and cAMP is not produced.
How does Gt pathway work?
Light causes GTP to act on cGMP PDE to convert cGMP to 5’-GMP.
How does Gq pathway work?
GTP binds PLC which increases intracellular Ca levels.
When epi binds to a beta adrenergic receptor, what happens? What signaling pathway?
Gs.
Relaxation on bronchial SM and intestinal SM.
Contraction of heart.
Increased mobilization of fuels.
What pathway does His target? What is the outcome?
Gs.
Bronchoconstriction and allergies.
What pathway does DA use? What is the outcome?
Gi.
Increased HR.
What pathway does ACh use? What is the outcome?
Gq.
Brochoconstriction and stimulation of salivary glands.
What is the anatomy of the RTK receptor?
Has an extra cellular domain that binds the ligand, a-helical transmembrane domain and an intracellular domain w/ TK activity
How does the RTK system work?
Ligand binds —> dimerization.
Dimerized receptor binds tyrosine.
Docking proteins recognize the RTK and trigger either a RAS-dependent or RAS-independent pathway.
What is the primary structure of insulin?
A chain and a B chain are linked by 2 disulfide bridges.
The A chain has its own disulfide bridge.
21 AAs in the A chain and 30 AAs in the B chain.
What is the active form of insulin?
What is the inactive form?
Active - hexamer
Inactive - monomer
How is insulin synthesized?
Preproinsulin mRNA —> preproinsulin protein —> translocated to ER lumen —> cleaved to form proinsulin —> folded in golgi —> released with C peptide.
2 phases of insulin release
- Rapid, but transient release. Comes from a limited pool of granules (<5%) known as the readily releasable pool.
- Second phase comes from the reserve pool (>95%). Granules here must undergo mobilization.
RAS-dependent insulin signaling (5))
Insulin binds to alpha subunit of insulin receptor (an RTK).
Autophosporylation of tyrosine residues in the beta subunit.
Insulin receptor substrate 1 (IRS-1) recognizes the phosphotyrosine residues.
GRB-2 recognizes IRS-1 and triggers the RAS and MAP kinase pathway.
Causes increased transcription of glucokinase.
Glucokinase phosphorylates glucose in the first step of glycolysis.
RAS-independent insulin signaling (5)
Insulin bind to RTK.
Autophosphorylation.
IRS-1 recognizes the RTK and is phosphorylated.
PI3kinase is recruited by IRS-1.
PIP2 and PIP3 are activated and stimulate recruitment of protein kinase B (PKB).
PKB stimulates glucose uptake/storage.
What is the role of PKB in the movement of GLUT 4?
It moves GLUT4 from cytoplasm to PM of muscle and adipose to allow Glc to enter.
How does PKB promote glycogen synthesis?
It inhibits glycogen synthase kinase 3 (GSK-3).
How is insulin signaling terminated?
The insulin receptor is internalized and degraded or recycled.
What is insulin resistance?
A down regulation of the insulin receptor.
What is the quantifiable parameter of insulin resistance?
Measure the amount of glucose cleared from the blood in response to a fixed dose of insulin.
Severe insulin resistance can be caused by?
Defects in insulin binding domain on extra cellular side or variations of intracellular domains.
Phosphorylation of which aa instead of tyrosine in the IR can inhibit activation and signaling?
Serine
What are orphan receptors?
Nuclear receptors discovered by DNA sequencing. Ligands are unknown.
3 major domains of nuclear receptors
Ligand binding domain (LBD)
Activation function 1 domain (AF1) (aka transcription activating domain)
DNA binding domain
What do DBDs bind?
HRE
Types of estrogen receptors (2)
ERa
ERbeta
Where is ER alpha expressed most?
Female reproductive tract and mammary gland, hypothalamus, endothelium and vascular sm
Where is ER-beta mostly expressed?
Ovaries and prostate
Which ER is believed to be predominant in growth regulation?
ER-alpha
What is the MOA of ER?
Estrogen binds and promotes his tone acetyl transferase (HAT) which activates transcription.
MOA of tamoxifen
Tamoxifen is metabolized by the liver to 4-hydroxy-tamoxifen —> promotes histone deacetylase activity (HDAC) —> inhibits transcription.
What is the general transcription apparatus (GTA) and what is its role in the ER and tamoxifen?
It enhances transcription.
ER recruits it, and tamoxifen tries to inhibit it.
ER has both:
Genomic and non-genomic effects (in cytoplasm and PM).
