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Block 5 > Pharm - Lecutre 3 - signal transduction > Flashcards

Pharm - Lecutre 3 - signal transduction Flashcards

0
Q

What does cortisol bind to once inside the target cell?

A

GR = glucocorticoid receptor

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1
Q

What carrier protein does cortisol bind to?

A

CBG

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2
Q

How does cortisol get into through the plasma membrane?

A

diffusion

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3
Q

What occurs after GR is bound by cortisol in the cytoplasm?

A

1) Cortisol causes a conformation change on the GR receptor,

2) This releases inhibitory proteins HSP70. The GR receptor is now free to diffuse into the nucleus

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4
Q

What occurs once once the active GR receptor diffuses into the nucleus?

A

The active receptor binds to a hormone response element (GRE = glucocorticoid response element)

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5
Q

What are the subunits of the Nicotinic acetylcholine receptor?

A

a1, a2, B, y, delta

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6
Q

What type of receptor are Nicotinic acetylcholine receptors?

Is this excitatory or inhibitory?

A

Ion channel-linked receptor

Excitatory

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7
Q

Where is the Nicotinic acetylcholine receptor located? (3)

A

1) Nueromuscular junction
2) peripheral autonomic nervous system
3) central nervous system

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8
Q

What type of receptor is the GABA receptor?

A

gated Cl- channel

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9
Q

What type of response is elicited from GABA receptors?

A

inhibitory - GABA is the main post-synaptic inhibitory transmitter in CNS

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10
Q

What affect does the activated GABA receptor have on the cell electrical state?

A

It allows Cl- and so hyperpolorizes the cell

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11
Q

How many times does the GCPR pass through the membrane?

A

7

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12
Q

What are the three subunits of G proteins and what are their function?

A

Ga: binds GT, binds effectors, acts as GTPase

Gbeta and Ggamma form the beta/gamma dimer and anchors to the membrane

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13
Q

What state of the G protein elicits an active response? What turns off this response?

A

GTP bound to the Galpha subunit occurs when activated

GTPase activity of the alpha subunit converts GTP to GDP and turns activity off

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14
Q

What are three types of Galpha proteins and what do they do?

A

1) Gas (stimulates adenylyl cyclase)
2) Gai (inhibits adenylyl cylcase)
3) Gaq (stimulates phospholipase C)

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15
Q

What are two possible structures of Tyrosine Kinase-Linked receptors?

A

1) single protein with one transmembrane domain

2) tetramer composed of 2 EC subunits and 2 transmembrane subunits

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16
Q

Where does the ligand bind a Tyrosine Kinase-Linked receptor?

A

EC domain

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17
Q

What occurs upon ligand binding to the Tyrosine Kinase-Linked receptor? (3)

A

1) dimerization
2) activation of cross-phosphorylation (the 2 cytoplasmic subunits phosphorylate each other
3) binding of intracellular signaling molecules

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18
Q

What are examples of serine/threoinine specific protein kinases? (4)

A

PKA
PKC
Ca2+/calmodulin dependent protein kinase
MAP kinases

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19
Q

What are examples of tyrosine specific protein kinases?

A

EGF receptor (and other tyrosine kinase-linked receptors)
Src,
Abl

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20
Q

What is an example of dual specificity protein kinase? What do these proteins phosphorylate?

A

Phosphorylate both threonine and tyrosine

MAP kinase kinase (MKK1)

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21
Q

What are examples of second messengers?

A

cAMP
DAG
IP3
Calcium

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22
Q

How is cAMP generated?

A

generated by adenyl cyclase when it is activated by Gas

23
Q

How is DAG and IP3 generated?

A

Generated when PLC cleaves PIP2 into DAG + IP3

24
Q

What is the signaling pathway for cAMP regulated by GPCRs?

A

1) ligand binds receptor
2) Gas binds GTP and dissociates from By subunits
3) Gas-GTP activates adenylyl cyclase
4) adenylyl cyclase converts ATP to cAMP
5) cAMP activates PKA
6) PKA phosphorylates and activates or inactivates an enzyme
7) enzyme makes (or stops making) products

25
Q

What is the structure of PKA?

A

Tetramer - 2 catalytic and 2 regulatory subunits

26
Q

How does PKA become active and what happens? (3 steps)

A

1) The R subunits each bind a cAMP molecule
2) The R and C subunits dissociate
3) C subunits become autophosphorylated and activated

What happens: C subunit phosphorylates proteins on Threonine and serine residues activating or inactivating them

27
Q

What is the difference between Gas activity and Gai? (2)

A

1) Gas stimulates adenylyl cyclase, Gai inhibits it

2) they are activated by different GPCR’s

28
Q

What inositol-lipid pathway? (5 steps)

A

1) ligand binds to and activates GPCR
2) Gaq binds GTP and dissociates from By subunits
3) Gaq-GTP activates phospholipase C (PLC)
4) PLC cleaves PIP2 to make DAG and IP3
5a) IP3 diffuses into cytoplasm and releases calcium from ER
5b) DAG remains attached to membrane and together with calcium, activates PKC

29
Q

How are Monomeric G proteins activated?

A

Monomeric G proteins are recruited to receptor linked-tyrosine kinase and turned on by GEF

30
Q

How are monomeric G proteins turned off?

A

Monomeric G proteins are recruited to receptor linked-tyrosine kinase and turned off by GAP

31
Q

What type of molecule is RAS?

A

monomeric G protein

32
Q

What type of molecule is SOS?

A

GEF

33
Q

How is RAS-GTP activated?

A

1) a ligand binds the tyrosine kinase receptor causing autophosphorylation
2) the receptor binds an adapter protein called GRB2
3) GRB2 activates Sos
4) Sos (a GEF) activates Ras (a monomeric G protein)
5) The GEF (sos in this case) causes Ras-GDP to release the GDP and bind GTP thus activating it

34
Q

How is Ras-GTP inactivated?

A

When Ras-GTP interacts with GAP, the GAP induces Ras-GTP’s inherent GTPase activity and GTP is hydrolyzed to GDP

35
Q

What activates Raf to begin the MAP Kinase signaling cascade?

A

Ras-GTP activates Raf

36
Q

What type of molecule is Raf?

A

a MAP kinase kinase kinase

37
Q

What are the steps for the MAP kinase signaling cascade starting from an activated Ras-GTP?

A

1) Ras-GTP activates Raf
2) Raf phosphorylates MKK1
3) MKK1 phosphorylates ERK
4) ERK phosphorylates many different transcription factors

38
Q

What type of molecule is MKK1?

A

MAP Kinase Kinase

39
Q

What type of molecule is ERK?

A

MAP kinase

40
Q

What type of receptor is the EGF receptor?

A

Tyrosine kinase receptor

41
Q

What would mutations in EGF receptor cause?

A

Abnormally high activity of the MAP kinase signaling cascade - promotes tumor growth

42
Q

What would mutations in Ras cause?

A

Abnormally high activity of the MAP kinase signaling cascade - promotes tumor growth

43
Q

What is the mechanism of gefitinib?

A

Inhibits signaling of the EGF receptor

44
Q

What is the mechanism of erlotinib?

A

Inhibits signaling of the EGF receptor

45
Q

What two drugs inhibit signaling of the EGF receptor?

A

1) gefitinib

2) erlotinib

46
Q

What determines the efficacy of gefitinib and erlotinib regarding tumor supression?

A

Efficacy is high if the tumor expresses a MUTATED EGF receptor. They don’t work as well (-10%) if the EGF receptor mutations are absent

47
Q

What are mechanisms of adaption? (2)

A

Receptor mediated endocytosis

Receptor desensitization

48
Q

What is adaption?

A

Modulation of signals in response to intensity and frequency of stimulation

49
Q

How is receptor mediated endocytosis carried about?

A

1) upon binding the ligand, receptors migrate to coated pits
2) the receptor is internalized
3) some receptors are recycled, some are degraded by lysosomes

50
Q

What is the role of clathrin?

A

clathrin is the structural protein that forms the electron dense cage that forms the vesicle that receptors are endocytosed in

51
Q

What is CURL?

A

the tubular-reticular structure that forms the compartment for receptor-ligand uncoupling

52
Q

What is the p.H. in CURL and why?

A

4.5 - 5 to favor dissociation of ligand and receptor

53
Q

What is retroendocytosis?

A

The recycling of endocytosed receptors

54
Q

What is homologous desensitization? What is the process? (2 steps)

A

The desensitization of the stimulated receptor

Process:

1) GPCR is phosphorylated by betaARK
2) beta arrestin binds to phosphorylated GPCR and inactivates it

55
Q

What is Heterologous desensitization? Mechanism?

A

Both the stimulated and unstimulated receptors are blocked

Mechanism:

1) phosphorylation of receptors
2) competition for shared second messengers

Block 5 (23 decks)

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