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Cell biology > Week 11: Cell signaling pt 2 > Flashcards

Week 11: Cell signaling pt 2 Flashcards

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1
Q

G-protein coupled receptors

A

7 transmembrane alpha helices with a C terminal that sticks out
- communicate info from the outside to the inside of the cell and are a major drug target for small molecule therapies
- they have a small pocket toward the outside of the receptor side where the ligand will bind

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2
Q

GPCR steps (5)

A
  1. ligand binding ⇒ anything that binds and activates
  2. Change in GPCR conformation
  3. Interaction with G protein heterotrimer
  4. GDP exchange for GTP (GEF)
  5. Activation of target proteins
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3
Q

heterotrimer

A

composed of an alpha, beta, and gamma subunits ⇒ refer to the G protein
- Binds with GDP switching to GTP in the G protein when active
- uses GEF to switch out GDP to GTP
- the alpha stays by itself and beta and gamma always stay together

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4
Q

common small molecules from active GPCR pathways

A

cAMP, IPX, K+, Ca2+

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5
Q

5 key facts of GPCR’s

A
  1. stimulation of GPCRs activates heterotrimeric G proteins
  2. some G proteins directly regulate ion channels
  3. some G proteins activate membrane bound enzymes
  4. cyclic AMP pathway can activate enzymes and turn on genes
  5. Inositol phospholipid pathway triggers a rise in cytosolic CA2+
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6
Q

heterotrimeric G proteins

A

(large G proteins) covalently bound to membrane lipids by their alpha and gamma subunits
Alpha subunit with bound GDP is inactive

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7
Q

What is like G proteins

A

Ras is similar to G proteins but are smaller

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8
Q

what attaches the G proteins to the cell membrane?

A

lipid modifications on both the alpha and beta/gamma portions
- when bound to GDP it is inactive

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9
Q

activation process of G proteins (4)

A
  1. Signal binds GPCR
  2. GDP to GTP exchange via GEF
  3. Release of G protein in active form
  4. Both alpha subunit and beta/gamma complex can interact wtih downstream targets
    - Activates G-proteins can be stimulatory (Gs) or inhibitory (Gi) ⇒ Gq is neither inhibitory or stimulatory
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10
Q

where does the GDP molecule binds in G proteins?

A

in the AH domain of the alpha subunit

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11
Q

what does the active G protein do?

A
  • Activated alpha subunit (with GTP) activates or inhibits the target and stays active until it is hydrolyzed ⇒ time delay from active to hydrolysis and during this window it keeps activating the effect
  • Active beta/gamma can also activate or inhibit the target
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12
Q

how do turn off the G protein

A

GTP hydrolysis terminates (via GAP) activation of G protein
- Inactivated alpha GDP subunits dissociate from target and reforms inactive G protein complex

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13
Q

cholera toxin (CTx)

A

binds to the G protein and modifies alpha subunit of stimulatory G proteins so they can no longer hydrolyze bound GTP ⇒ signals cannot be turned off

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14
Q

what does cholera toxin shut off?

A

Shuts off the GAP activity which prevents hydrolysis leading to cAMP which impacts CFTR regulating Cl- kept in the cell

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15
Q

what is the effect of cholera toxin?

A

Causes excessive outflow of Cl- and H2O into gut, leading to diarrhea and dehydration
- As Cl- goes out so does sodium in the cell junctions with water ⇒ lose sodium and water from the system

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16
Q

how is cholera toxin treated?

A

you treat cholera with antibiotics but also electrolytes filled with NaCl

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17
Q

what secondary molecules are influenced by cholera toxin?

A

works in GalphaS to keep it active in GTP state which activates adenylyl cyclase to increase cAMP

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18
Q

pertussis toxin (Ptx)

A

modified alpha subunit of inhibitory G-proteins and locks them into inactive GDP bound state
- Inhibiting an inhibitory G-protein results in prolonged signaling that stimulates coughing (whooping cough)

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19
Q

what does pertussis toxin keep inactive?

A

it works on Galpha to keep it inactive in the GDP bound state

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20
Q

what effect does pertussis toxin have on second messengers?

A

it inhibits adenylyl cyclase which increases cAMP because it inhibits adenylyl cyclases inhibitor

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21
Q

which 4 G proteins decide downstream pathways?

A
  1. Gbeta-gamma
  2. GalphaS
  3. GalphaQ
  4. GalphaT aka transducin
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22
Q

Gbeta-gamma

A

activates ion channels

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23
Q

GalphaS

A

activates adenylyl cyclase which makes cAMP

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24
Q

GalphaQ

A

activates inositol phosphate which activates calcium signaling

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25
Q

GalphaT

A

affects photoreceptor signaling

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26
Q

process of how Gbeta-gamma regulates potassium channels? (5) What’s the result?

A
  • Ligand is acetylcholine (Ach) binds GPCR
  • Activates G-protein
  • Active beta/gamma complex to stimulate opening of K+ ion channel ⇒ K+ goes out
  • GTP hydrolysis inactivates G-protein
  • K+ channel closes
    → Results in relaxation of the muscle cells
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27
Q

which G protein activates membrane bound enzymes?

A

GalphaS G protein gets activated by GPCR and then activates adenylyl cyclase (attached to it) which takes ATP and converts it to cAMP

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28
Q

were GPCRs or G proteins found first by Nobel prize winners?

A

G proteins were first by Gilman after Rodbell discovered cAMP
- GPCRs were discovered later in 2012

29
Q

adenylyl cyclase

A

converts ATP to cyclic AMP, cAMP activates targets
- Take out 2 phosphate and grab the remaining phosphate to be stitched toward the back of the molecule ⇒ 1 phosphate remains
- Starts the signal and amplifies the signal

30
Q

cAMP phosphodiesterase

A

converts cAMP to AMP to terminate a signal
- Some G-proteins stimulate adenylyl cyclase, others inhibit

31
Q

what does caffeine inhibit?

A

phosphodiesterase which prolongs cAMP signaling in the nervous system
- cAMP has many important targets

32
Q

how does cAMP signaling in skeletal muscles work?

A
  • Adrenaline activates the GPCR protein which activates GalphaS connected to adenylyl cyclase
  • GalphaS Stimulates adenylyl cyclase to make cAMP
    cAMP activates PKA
  • PKA activates a phosphorylase kinase which causes a phosphorylation cascade
  • Stimulates glycogen breakdown to glucose for energy in muscle via glycogen phosphorylase
33
Q

is adrenaline fast or slow acting?

A

fast

34
Q

adrenaline

A

fight or flight and binds to a GPCR

35
Q

how does cAMP work to turn on genes?

A
  • same original pathway as adrenaline activated by a signaling molecule and then activates GalphaS and adenylyl cyclase
  • adenylyl cyclase makes cAMP which binds PKA
  • Active PKA goes to nucleus
  • PKA activates CREB via phosphorylation
  • CREB recruits a CREB binding protein (CBP) which binds to the cAMP response element (CRE)
  • this binding induces gene transcription of the target gene
36
Q

what does Pi transcription factor (CREB) do?

A

stimulates transcription and effects depend on cell types and specific transcription factors affected ⇒ is the transcription factor
- Convert short term signals into long term response

37
Q

what does the slow cAMP/PKA pathway result in? (2)

A
  • Secretion of hormones in endocrine system
  • Learning and memory in brain ⇒ encode changes to remember what the event was
38
Q

what are downstream of GaphaS? (4)

A
  • Activation of adenylyl cyclase to produce cAMP (fast)
  • Activation of PKA to phosphorylate CREB (slow)
  • Activation of PKA to phosphorylate phosphorylase kinase (fast)
  • Translocation of PKA to the nucleus (slow)
39
Q

what is the inositol phospholipid pathway? (5)

A
  • a ligand binds GPCR
  • this activates GalphaQ
  • this activates phospholipase C-beta to cleave IP3 from PI(4,5)P2 lipid in the membrane (results in diacylglycerol in the membrane still)
  • the cleaves IP3 stimulates calcium channels to open in the ER membrane and to activate protein kinase C binding to diacylglycerol
  • calcium floods out of the ER lumen and binds to protein kinase C attached to diacylglycerol on the plasma membrane
40
Q

PLC beta

A

lipase that cleaves a lipid by cutting off the IP3 unit off of PI(4,5)P2 leaving the diacylglycerol portion in the plasma membrane

41
Q

what is protein kinase A downstream of vs protein kinase C?

A

protein kinase A is downstream of cAMP and protein kinase C is downstream of IP3 and Ca2+

42
Q

diacylglycerol

A

binds a kinase called protein kinase C

43
Q

second messenger

A

any intermediate that is amplifying the signal

44
Q

how to turn off the G protein signal?

A

when activated, the GPCR can be phosphorylated by a GPCR kinase (GRK) which attracts arresting to block the signal from continuing

45
Q

receptor tyrosine kinases (RTKs)

A

comes from the receptor itself being a kinase
- There are 2 receptors on the membrane which are separate from one another
- the knob is the tyrosine kinase domain

46
Q

how do RTK’s work?

A

Signal growth factor (protein) binds and then dimerizes the receptor to bring the two together
- The tyrosine kinase trans-autophosphorylation one another leading to the receptor being active ⇒ the kinase is not active so it can phosphorylate other sites for binding
- Phosphorylated sites allow for scaffolding of other adaptor proteins which bring something else onto the scaffold
- end goal is to relay the signal downstream leading to what the receptor is propagating

47
Q

what do growth factors signal through?

A

RTKs => most have a growth factor in the name because activation of the receptor stimulates growth and division
- Often increases protein synthesis, proliferation (cell division), growth, and survival

48
Q

RTKs have structural diversity T/F?

A

True
1. Comes from having diverse extracellular domains ⇒ sizes and types
2. All share the tyrosine kinase domain on the inside of the cell membrane

49
Q

EGFR RTK activation process?

A
  • EGF is the ligand that binds to activate the RTK
  • There is a receiver kinase and an activator kinase
  • Once the C terminal tail is phosphorylated, these will scaffold other proteins
50
Q

there are different phosphorylated tyrosine sites that go on to do what?

A

recruit different downstream proteins

51
Q

Ras

A

a monomeric G-protein anchored to the membrane
- Ras-GTP activates many downstream targets and mutations in Ras account for a vast majority of cancer

52
Q

steps for activating Ras

A
  1. Activated RTK
  2. Grb2 adaptor recruits another adaptor Sos (2 different proteins)
  3. There are SH3 proteins which are universal adaptors between two proteins
  4. Sos has a Ras GEF domain (GEF for Ras as the inactive G protein) which is different from the larger G proteins
    - Has GDP sitting on the membrane and is activated from GDP getting exchanged for GTP
53
Q

a signaling protein only made up of one SH2 domain and 2 SH3 domains is likely what?

A

an adaptor protein => SH2 and SH3 domains are a hallmark of adaptors

54
Q

what is Ras known to activate?

A

MAPK => mitogen activated protein kinase

55
Q

mitogens

A

something that causes mitosis
- There must be something that phosphorylates the MAP kinase

56
Q

Ras activates ___ which activates ____

A

Ras activates Mek which activates Erk
- Blockbuster drugs target Ras when you get a melanoma

57
Q

ERK1/2

A

a key stimulator of cell growth and proliferation
- the end goal is that you activate other proteins and trigger gene expression

58
Q

how does activation of PIP3 signaling happen?

A
  • RTK activates PI 3-kinase and Pi 3-kinase converts membrane bound PIP2 to PIP3 (lipid) => If you cut off the phosphate you get diacylglycerol and if you add a phosphate you get PIP
  • PIP3 acts as a second messenger and recruits protein kinase 1 and Akt kinase (PKB) which scaffold mTOR
  • Akt kinase promotes cell survival and cell growth by splitting the Bcl2 and Bad
59
Q

Akt kinase phosphorylates which protein? This does what?

A

Bad; this releases Bcl2 and binds 14-3-3 adaptor protein so that active Bcl2 inhibits apoptosis

60
Q

what is the mTOR pathway?

A
  • activated RTK activates PI 3-kinase to activate AKT
  • AKT inhibits TSC which is Rheb’s GAP protein
  • TSC cannot hydrolyze Rheb to turn off the signal so Rheb can now activate mTOR which stimulates cell growth
61
Q

alternative mTOR pathway?

A
  • activated RTK activates Ras which activates Erk (MAPK)
  • ERK inhibits TSC which is Rheb’s GAP protein
  • TSC cannot hydrolyze Rheb to turn off the signal so Rheb can now activate mTOR which stimulates cell growth
62
Q

Rheb

A

when this is bound to GTP it activates the mTOR complex which stimulates growth

63
Q

Growth

A

refers to a cell getting bigger

64
Q

proliferation

A

refers to the cell multiplying

65
Q

Rapamycin

A

has an ability to inhibit mTOR and can be used to suppress the immune system

66
Q

mTOr in complex 1 contains the protein raptor which is sensitive to rapamycin and stimulates cell growth T/F?

A

True

67
Q

rapamycin (sirolimus) is used as an immunosuppressant for preventing organ transplant rejection T/F?

A

True

68
Q

Akt activates mTOR in complex by activating a Rheb-Gab called Tsc2 T/F?

A

False

69
Q

mTOR in complex 1 is activated in the presence of growth factors T/F?

A

True

Cell biology (15 decks)

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