Hormone Signaling Pathways

Question 1

How is cell signalling generally terminated?

Answer 1

by removal of signaling molecule or receptor

or attenuation/inactivation of signaling events

Question 2

What is juxtacrine signaling?

Answer 2

signaling molecule stays attached to the secreting cell and binds a receptor on an adjacent targent cell

Question 3

How is hydrophilic hormone signaling accomplished?

Answer 3

hydrophilic signal binds receptor at cell surface –> molecule-receptor complex initiates production of second messenger molecules –> cellular response

main receptors = GPCRs, RTKs

Question 4

How do lipophilic hormones signal?

Answer 4

passively diffuse through plasma membrane of target cell –> bind receptor in PM or on nucleus –> acts as a transcription factor

Question 5

What are the main hydrophilic hormones?

Answer 5

amines: histamine, SE, melatonin, dopamine, NE, epi

From lipid metabolism: Ach

Polypeptides: insulin, glucagon, cytokines, TSH

Question 6

What are the main lipophilic hormones?

Answer 6

steroids: progesterone, estradiol, testosterone, cortisol, aldosterone, Vit D

Thyroid hormone

retinoids

Question 7

What is the difference in half-lives of hydrophilic and lipophilic hormone medications?

Answer 7

hydrophilic = short half lives

lipophilic = long, slow acting

Question 8

What are the basics of GPCR signaling?

Answer 8

inactive trimeric G protein –> GEF exchanges GDP for GTP –> gamma and beta leave = active –> GAP removes Pi –> inactive trimeric w/ GDP

Question 9

What does a Gs receptor do?

Answer 9

stimulates adenylate cyclase –> cAMP –> PKA –> other proteins phosphorylated

Question 10

What does a Gi receptor do?

Answer 10

inhibits Adenylate cyclase –> no cAMP produced

Question 11

What does a Gt receptor do?

Answer 11

light –> GPCR –> cGMP phosphodiesterase

Question 12

What does a Gq receptor do?

Answer 12

Gq –> PLC –> IP3 and DAG –> Ca and PKC

Question 13

What kind of receptor does histamine bind?

Answer 13

Gs

Question 14

What kind of receptor does Ach bind?

Answer 14

Gq

Question 15

What kind of receptor does dopamine bind?

Answer 15

Gi

Question 16

What is the general structure of an RTK?

Answer 16

extracellular domain

alpha-helical transmembrane domain

intracellular TK domain

Question 17

How does RTK signaling generalling work?

Answer 17

ligand binds to extracellular domain –> dimerization –> tyrosines Piate –> recognize adaptor proteins –> RAS-dependent and RAS-independent paths

both Piate spec proteins

Question 18

What is the basic structure of insulin?

Answer 18

A chain = 21 aa

B chain = 30 aa

connected by 2 disulfide bridges

1 disulfide bridge within A chain

Question 19

What is the difference btw inactive and active insulin?

Answer 19

inactive = stored in body as a hexamer

active = monomer

Question 20

How is insulin synthesized?

Answer 20

preproinsulin mRNA –> preproinsulin protein –> goes to ER –> cleaved to proinsulin –> folded and moved to golgi –> packaged and cleaved in golgi –> mature granules = hexameric crystals (3 dimers)

Question 21

What are the 2 pools of insulin corresponding phases of insulin release?

Answer 21

readily releasable pool = limited, 5%

reserve pool = 95%, granules must undergo mobilization

Question 22

What does the RAS-dependent signaling of insulin do?

Answer 22

insulin binds RTK –> GRB-2 and IRS-1 –> RAS –> Piated proteins –> alterations in gene transcription (increased scrip of glucokinase –> glucose uptake, glucogen synthesis

Question 23

What does the RAS-independent insulin signaling do?

Answer 23

insulin binds RTK –> Pi 3-kinase –> PKB –> Piated proteins –> alterations in protein and enzyme activity (more glut4, activation of glycogen synthase) –> glucose uptake, glycogen synthesis

Question 24

How is insulin signaling terminated?

Answer 24

insulin-receptor complex is internalized in target cells by endocytosis –> either degraded or recycled

Question 25

How does insulin affect its own receptor?

Answer 25

downregulates its receptor decreases rate of synthesis/increases rate of degradation

Question 26

How is insulin resistance quantified?

Answer 26

amount of glucose cleared from the blood in response to a fixed dose of insulin --\> failure of expected response = resistance

Question 27

What are the 3 main possibilities for insulin resistance currently being studied?

Answer 27

downregulation of insulin receptor defects in insulin signaling (less GLUT4) defects in insulin receptor (75 mutations ID'd)

Question 28

What are the main defects in downstream insulin receptor signaling being studied?

Answer 28

defects in IRS1 and IRS2 **Piation of serine instead of tyr** in IR and IRS --\> inhibits downstream signaling **Ser/Thr kinase** activated by cytokines, FFAs, DAG, ceramide, etc --\> impairs downstream signaling

Question 29

Where are nuclear receptors

Answer 29

in nucleus or in cytosol --\> translocate to nucleus after ligand binds

Question 30

What are the 3 major domains of nuclear receptors?

Answer 30

ligand binding domain (LBD) activation function 1 domain (AF1) aka transcription activating domain DNA binding domain (DBD)

Question 31

What does AF1 on a nuclear receptor do?

Answer 31

independent of ligand binding can modify conformation of entire receptor

Question 32

What does DBD on a nuclear receptor do?

Answer 32

highly conserved binds regulatory seq on DNA = hormone response elements (HREs) upstream of target gene

Question 33

What are the primary and secondary responses to steroid hormones?

Answer 33

primary = proteins directly induced from steroid-receptor complex secondary = primary protein shuts off its own genes --\> turns on secondary response genes

Question 34

What is ERalpha and where is it found?

Answer 34

estrogen receptor = transcription factor expressed most abundantly in female repro tract also in mammary gland, hypothalamus, endothelial cells, and vasc smooth muscle

Question 35

What is ERbeta and where is it found?

Answer 35

estrogen receptor = transcription factor expressed most in ovaries, prostate, w/ lower expression in lung, brain, bone, and vasculature

Question 36

What is the mechanism of action of ER?

Answer 36

estrogen binds --\> ER dimerizes --\> promotes HAT activity --\> activates transcription

Question 37

How does tamoxifen work?

Answer 37

metabolized by liver to 4-hydroxy-tamoxifen --\> inhibits ER --\> promotes HDAC activity --\> inhibits transcription

Question 38

Where is ER located?

Answer 38

traditionally thought to be in the nucleus some evidence that it is in the cytosol estrogen binding --\> dimerization and translocation to nucleus

Question 39

What are the non-genomic ER signaling pathways?

Answer 39

some ERs located in the plasma membrane or caveolae in plasma membrane GPCR and RTK type of receptors metabolic changes

Question 40

What hormones use a Gs receptor?

Answer 40

GCAPALT glucagon calcitonin ACTH PTH ADH (V1 receptor) LH and FSH TSH

Question 41

What hormones use a Gq receptor?

Answer 41

GAGOAT GHRH Angiotensin II GHRH Oxytocin ADH (V2 receptor) TRH

Question 42

What hormones use an RTK to signal?

Answer 42

PIGI prolactin insulin GH IGF-1