Hormone Signaling Pathways Flashcards

1
Q

Define: signaling molecule released by one cell type and diffuses to a neighboring target cell of a different cell type

A

Paracrine signaling

ex. testosterone

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2
Q

Define: signaling molecule acts on the same cell type as the secreting cells themselves

A

autocrine signaling

ex. IL-1

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3
Q

Define: signaling molecule stays attached to secreting cell and binds to a receptor on an adjacent target cell

A

Juxtacrine signaling

ex. heparin-binding epidermal growth factor

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4
Q

________ hormones cannot penetrate the plasma membrane

A

hydrophilic

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5
Q

What are the receptors involved in hydrophilic hormone signaling?

A

GPCRs

RTKs

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6
Q

________ hormone passes through plasma membrane of target cell

A

lipophilic

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7
Q

What are the examples of hydrophilic hormones?

A

Epinephrine
Insulin
Glucagon

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8
Q

What are the examples of lipophilic hormones?

A

Steroid hormones, thyroid hormone and retinoids

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9
Q

What are cytoplasmic receptors ?

A

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

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10
Q

What are nuclear receptors

A

Already present in nucleus bound to DNA

Hormone signal activates the complex and allows for interactions with additional proteins

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11
Q

Describe the half life of hydrophilic medications and give an example

A

Short half lives

Epinephrine - contained in autoinjectors used to treat severe acute allergic reaction that may lead to anaphylatic shock

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12
Q

Describe the half life of lipophilic medications

Give an example

A

Long half lives

Oral contraceptives - contain ethinyl estradiol, a derivative of estradiol

Need to take daily

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13
Q

Describe GPCR signaling

A

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

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14
Q

Describe Gs GPCRs

A

Stimulates adenylate cyclase

ATP-> cAMP

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15
Q

Describe Gi GPCRs

A

inhibits adenylate cyclase

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16
Q

Describe Gt GPCRs

A

Stimulate hydrolysis of cGMP

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17
Q

Describe GPCR signaling via Gq

A

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)

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18
Q

What hormone activates GPCRs via Gs? What are the effects?

A

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.

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19
Q

Histamine activates what kind of GPCRs. What are the effects?

A

Gs

*bronchoconstriction and symptoms of allergic reactions

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20
Q

Epinephrine and NE activate what kind of GPCRs? What are the effects?

A

Gi

*constriction of sm m

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21
Q

Why does epinephrine have such wide range of effects?

A

it is a non-selective agonist of all adrenergic receptors (major subtypes alpha1, alpha2, beta-1, -2, and -3)
Undergo multiple GPCR signaling pathways

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22
Q

Epinephrine beta activates what Type of GPCR?

A

Gs

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23
Q

Epinephrine alpha 2 activates what type of GPCR?

A

Gi

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24
Q

Epinephrine alpha 1 activates what type of GPCR?

A

Gq

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25
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
26
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
27
What is the active form of insulin?
a monomer
28
What upregulates preproinsulin mRNA?
glucose
29
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
30
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
31
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
32
Through what transporter does glucose enter beta cells?
GLUT 2
33
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
34
Define: Signaling molecule released by a cell distant from the target cell and transported via bloodstream to target cell
Endocrine signaling ex. epinephrine
35
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
36
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
37
What is quantifiable parameter measured as?
The amount of glucose cleared from the blood in response to a dose of insulin
38
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
39
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)
40
What is Ser/Thr kinase activated by?
cytokines, free FA, DAG, ceramide, inflammatory molecules
41
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
42
Type of diabetes: deficiency in insulin production
Type 1
43
Type of diabetes: insensitivity to insulin
Type 2
44
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
45
How does epinephrine stimulate breakdown of glycogen?
by promoting glucagon secretion
46
What hormone is released when glycogen stores are depleted?
cortisol - stimulates gluconeogenesis by inducing transcription of enzymes involved in pathway
47
What are the classic steroid nuclear receptors ligands?
ligands are lipophilic hormones | exx. GR, MR, ER, PR, AR
48
What are orphan receptors?
receptors discovered by DNA sequencing but ligands are unknown
49
What are the 3 major domains of nuclear receptors?
Activation function 1 domain DNA binding domain Ligand binding domain
50
_____ domain is independent of ligand binding, can modify the conformation of the entire receptor
AF1
51
______ is highly conserved, bind to regulatory sequences on DNA called HRE, upstream of target gene
DNA binding domain (DBD)
52
_____ binds various molecules (agonist or antagonist) which regulates ligand-dependent activation of receptor.
LBD (ligand binding domain)
53
Upon ligand binding a region within LBD (AF2), what occurs?
undergoes conformational changes allowing recruitment and binding of coactivators or corepressors that regulate transcription
54
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
55
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
56
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
57
Describe ERb
expressed most abundantly in prostate and ovaries, with lower expression in lung, brain, bone and vasculature
58
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
59
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
60
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
61
What inhibits the enzyme phosphodiesterase?
Caffeine
62
What triggers the Gt GPCR?
light