Hormone Signaling Pathways Flashcards
Define: signaling molecule released by one cell type and diffuses to a neighboring target cell of a different cell type
Paracrine signaling
ex. testosterone
Define: signaling molecule acts on the same cell type as the secreting cells themselves
autocrine signaling
ex. IL-1
Define: signaling molecule stays attached to secreting cell and binds to a receptor on an adjacent target cell
Juxtacrine signaling
ex. heparin-binding epidermal growth factor
________ hormones cannot penetrate the plasma membrane
hydrophilic
What are the receptors involved in hydrophilic hormone signaling?
GPCRs
RTKs
________ hormone passes through plasma membrane of target cell
lipophilic
What are the examples of hydrophilic hormones?
Epinephrine
Insulin
Glucagon
What are the examples of lipophilic hormones?
Steroid hormones, thyroid hormone and retinoids
What are cytoplasmic receptors ?
exist in an inactive complex with HSP 90
Upon binding to signal, HSP dissociates
Hormone-receptor complex translocates to nucleus where it binds to a specific DNA sequence called HRE (hormone response element) in promoter region of specific genes
What are nuclear receptors
Already present in nucleus bound to DNA
Hormone signal activates the complex and allows for interactions with additional proteins
Describe the half life of hydrophilic medications and give an example
Short half lives
Epinephrine - contained in autoinjectors used to treat severe acute allergic reaction that may lead to anaphylatic shock
Describe the half life of lipophilic medications
Give an example
Long half lives
Oral contraceptives - contain ethinyl estradiol, a derivative of estradiol
Need to take daily
Describe GPCR signaling
Trimeric G proteins: alpha, beta, gamma
Inactive G protein with GDP bound to alpha
Activated by GEF: GDP->GTP
Inactive again: intrinsic GTPase activity or accelerate inactivation by GAP
Describe Gs GPCRs
Stimulates adenylate cyclase
ATP-> cAMP
Describe Gi GPCRs
inhibits adenylate cyclase
Describe Gt GPCRs
Stimulate hydrolysis of cGMP
Describe GPCR signaling via Gq
Alpha-GTP activates PLC
PIP2 cleaved into IP3/DAG
IP3 opens Ca channels from ER/SR
Ca translocates PKC to plasma membrane
DAG activates PKC
Ca binds to calmodulin to activate CaM kinase (alters protein activity) and MLC kinase (phosphorylates myosin light chains, sm m contraction)
What hormone activates GPCRs via Gs? What are the effects?
Epinephrine
*relaxation of bronchial and intestinal sm m
contraction of heart m
increase breakdown of TG in adipose tissue, glycogen in liver and m
and increase glycolysis in m.
Histamine activates what kind of GPCRs. What are the effects?
Gs
*bronchoconstriction and symptoms of allergic reactions
Epinephrine and NE activate what kind of GPCRs? What are the effects?
Gi
*constriction of sm m
Why does epinephrine have such wide range of effects?
it is a non-selective agonist of all adrenergic receptors (major subtypes alpha1, alpha2, beta-1, -2, and -3)
Undergo multiple GPCR signaling pathways
Epinephrine beta activates what Type of GPCR?
Gs
Epinephrine alpha 2 activates what type of GPCR?
Gi
Epinephrine alpha 1 activates what type of GPCR?
Gq
Describe the primary structure of insulin
two peptide chains (A chain and B chain)
Linked together by 2 disulfide bridges and an additional disulfide is formed within A chain
In most sspecies the A chain consists of 21 aa and B chain of 30 aa
What is the inactive form of insulin?
6 insulin molecules assembled in a hexamer and stored
3-fold symmetry with zinc in the center connected to polypeptide via hisidines
What is the active form of insulin?
a monomer
What upregulates preproinsulin mRNA?
glucose
Describe the steps to activate insulin
Preproinsulin has N terminal hydrophobic signal peptide that interacts with signal recognition particle that directs it ti ER
Translocated into lumen of ER
cleaved by protease to form proinsulin
Folds into correct conformation and 3 disulfides added w chaperone help
Transported into Golgi
packaged into immature clathrin-coated granules
Cleaved by PC1 and 2 and carboxpeptidase to form insulin
Insulin and C peptide released together
Describe readily releasable pool
After glucose stimulation - Accounts for first release phase that is rapidly initiated by transient
Limit pool of granules ready for immediate release
Describe reserve pool
After glucose stimulation, most insulin granules are responsible for second-phase of insulin secretion
Must undergo mobilization before they can gain release competence
Through what transporter does glucose enter beta cells?
GLUT 2
What do high levels of ATP/ADP inhibit in beta cells? What results?
K channels
This depolarizes the membrane
brings ca to inside the cell via Ca channel
Then the Ca causes Insulin granules to fuse with the membrane releasing insulin
Define: Signaling molecule released by a cell distant from the target cell and transported via bloodstream to target cell
Endocrine signaling
ex. epinephrine
Describe the insulin Ras-dependent signaling pathway
Dimerized RTK Insulin receptor autophosphorylates
IRS-1 recruited
GRB-2
RAS MAP
Alterations in gene transcription
e.g., increased transcription of glucokinase: phosphorylates glucose in first step of glycolysis
Describe the insulin Ras-independent signaling pathway
Dimerized RTK Insulin receptor autophosphorylates IRS-1 recruited PI 3 - kinase PIP3: second messengers and recruit PKB PKB phosphorylated and activated
Alteration in protein and enzyme activity
e.g. GLUT 4 movement to plasma membrane, promote glycogen synthesis by inhibiting glycogen synthase kinase 3
What is quantifiable parameter measured as?
The amount of glucose cleared from the blood in response to a dose of insulin
What is insulin resistance?
failure of normal amounts of insulin to elicit expected response
Defects in insulin signaling
more than 75 different mutations in insulin receptor identified
Extracellular side and intracellular domain variations cause severe resistance
Increased phosphorylation of ________ instead of tyrosine in the IR and IRS causes inhibition of activation and signaling and instead leads to degradation
serine (via ser/thr kinase)
What is Ser/Thr kinase activated by?
cytokines, free FA, DAG, ceramide, inflammatory molecules
Under fed conditions, what is the role of insulin?
Lower blood glucose by promoting glycogen synthesis, stimulating glycolysis, and inhibiting the activity and synthesis of enzymes for gluconeogenesis
Type of diabetes: deficiency in insulin production
Type 1
Type of diabetes: insensitivity to insulin
Type 2
How does glucagon increase blood sugar level? where is it released from?
By promoting breakdown of glycogen in liver and inhibiting glycogen synthesis
From the pancreas under conditions of glucose deficiency
How does epinephrine stimulate breakdown of glycogen?
by promoting glucagon secretion
What hormone is released when glycogen stores are depleted?
cortisol - stimulates gluconeogenesis by inducing transcription of enzymes involved in pathway
What are the classic steroid nuclear receptors ligands?
ligands are lipophilic hormones
exx. GR, MR, ER, PR, AR
What are orphan receptors?
receptors discovered by DNA sequencing but ligands are unknown
What are the 3 major domains of nuclear receptors?
Activation function 1 domain
DNA binding domain
Ligand binding domain
_____ domain is independent of ligand binding, can modify the conformation of the entire receptor
AF1
______ is highly conserved, bind to regulatory sequences on DNA called HRE, upstream of target gene
DNA binding domain (DBD)
_____ binds various molecules (agonist or antagonist) which regulates ligand-dependent activation of receptor.
LBD (ligand binding domain)
Upon ligand binding a region within LBD (AF2), what occurs?
undergoes conformational changes allowing recruitment and binding of coactivators or corepressors that regulate transcription
Describe primary and secondary response to steroid hormone
Steroid and its receptor induces synthesis of primary-response proteins
these proteins shut off primary-response genes and turns on secondary response genes
What are the two major types of estrogen receptors?
ERa and ERb
both are estrogen-dependent transcription factors
products of 2 separate genes located on different chromosomes but are similar in structure
ERb can substitute for ERa in some pathways
final biological effect mediated by ratio of 2 forms
Both expressed in breast cancers
Describe ERa
expressed most abundantly in female repro tract especially in uterus, vagina, and ovaries
Also mammary glands, hypothalamus, endothelial cells and vascular sm m
Describe ERb
expressed most abundantly in prostate and ovaries, with lower expression in lung, brain, bone and vasculature
What is an antagonist to Estrogen receptor pathway?
tamoxifen - used to treat breast cancer
binds to ER
Low affinity but metabolized by Cyt P450 (liver 1st pass) to create 4-hydroxy-tamoxifen to increase affinity 40x
Inhibits transcription by recruiting proteins such as histone deacetylase I - stabilizes nucleosome and prevents interaction with GTA
Describe the genomic effects of ERs
ER exists as monomer in nucleus
Ligand binds to receptor causing it to dimerize and interact with ERE in DNA
ER-DNA complex recruits co-activators that modify chromatin
Histone acetyltransferase activity (HAT) further alters chromatin structure
Recruiting proteins that comprise general transcription apparatus leading to mRNA synthesis
*Some evidence, ER located in cytosol, Estrogen binding causes dimerization and translocates
What are the non-genomic ER signaling pathways
Some ERs located in plasma membrane
Some present in caveolae (cholesterol-enriched domains in plasma membrane)
GPCR and RTK type
Effects mediated through metabolic changes as well as changes in gene expression
What inhibits the enzyme phosphodiesterase?
Caffeine
What triggers the Gt GPCR?
light
