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Endocrine - MSI Spring > Hormone Signaling Pathways > Flashcards

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
Q

Describe the primary structure of insulin

A

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
Q

What is the inactive form of insulin?

A

6 insulin molecules assembled in a hexamer and stored

3-fold symmetry with zinc in the center connected to polypeptide via hisidines

27
Q

What is the active form of insulin?

A

a monomer

28
Q

What upregulates preproinsulin mRNA?

A

glucose

29
Q

Describe the steps to activate insulin

A

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
Q

Describe readily releasable pool

A

After glucose stimulation - Accounts for first release phase that is rapidly initiated by transient
Limit pool of granules ready for immediate release

31
Q

Describe reserve pool

A

After glucose stimulation, most insulin granules are responsible for second-phase of insulin secretion
Must undergo mobilization before they can gain release competence

32
Q

Through what transporter does glucose enter beta cells?

A

GLUT 2

33
Q

What do high levels of ATP/ADP inhibit in beta cells? What results?

A

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
Q

Define: Signaling molecule released by a cell distant from the target cell and transported via bloodstream to target cell

A

Endocrine signaling

ex. epinephrine

35
Q

Describe the insulin Ras-dependent signaling pathway

A

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
Q

Describe the insulin Ras-independent signaling pathway

A 
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
Q

What is quantifiable parameter measured as?

A

The amount of glucose cleared from the blood in response to a dose of insulin

38
Q

What is insulin resistance?

A

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
Q

Increased phosphorylation of ________ instead of tyrosine in the IR and IRS causes inhibition of activation and signaling and instead leads to degradation

A

serine (via ser/thr kinase)

40
Q

What is Ser/Thr kinase activated by?

A

cytokines, free FA, DAG, ceramide, inflammatory molecules

41
Q

Under fed conditions, what is the role of insulin?

A

Lower blood glucose by promoting glycogen synthesis, stimulating glycolysis, and inhibiting the activity and synthesis of enzymes for gluconeogenesis

42
Q

Type of diabetes: deficiency in insulin production

A

Type 1

43
Q

Type of diabetes: insensitivity to insulin

A

Type 2

44
Q

How does glucagon increase blood sugar level? where is it released from?

A

By promoting breakdown of glycogen in liver and inhibiting glycogen synthesis

From the pancreas under conditions of glucose deficiency

45
Q

How does epinephrine stimulate breakdown of glycogen?

A

by promoting glucagon secretion

46
Q

What hormone is released when glycogen stores are depleted?

A

cortisol - stimulates gluconeogenesis by inducing transcription of enzymes involved in pathway

47
Q

What are the classic steroid nuclear receptors ligands?

A

ligands are lipophilic hormones

exx. GR, MR, ER, PR, AR

48
Q

What are orphan receptors?

A

receptors discovered by DNA sequencing but ligands are unknown

49
Q

What are the 3 major domains of nuclear receptors?

A

Activation function 1 domain
DNA binding domain
Ligand binding domain

50
Q

_____ domain is independent of ligand binding, can modify the conformation of the entire receptor

A

AF1

51
Q

______ is highly conserved, bind to regulatory sequences on DNA called HRE, upstream of target gene

A

DNA binding domain (DBD)

52
Q

_____ binds various molecules (agonist or antagonist) which regulates ligand-dependent activation of receptor.

A

LBD (ligand binding domain)

53
Q

Upon ligand binding a region within LBD (AF2), what occurs?

A

undergoes conformational changes allowing recruitment and binding of coactivators or corepressors that regulate transcription

54
Q

Describe primary and secondary response to steroid hormone

A

Steroid and its receptor induces synthesis of primary-response proteins
these proteins shut off primary-response genes and turns on secondary response genes

55
Q

What are the two major types of estrogen receptors?

A

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
Q

Describe ERa

A

expressed most abundantly in female repro tract especially in uterus, vagina, and ovaries
Also mammary glands, hypothalamus, endothelial cells and vascular sm m

57
Q

Describe ERb

A

expressed most abundantly in prostate and ovaries, with lower expression in lung, brain, bone and vasculature

58
Q

What is an antagonist to Estrogen receptor pathway?

A

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
Q

Describe the genomic effects of ERs

A

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
Q

What are the non-genomic ER signaling pathways

A

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
Q

What inhibits the enzyme phosphodiesterase?

A

Caffeine

62
Q

What triggers the Gt GPCR?

A

light

Endocrine - MSI Spring (15 decks)

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