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Core course > Exam 4 > Flashcards

Exam 4 Flashcards

1
Q

what was the first second messenger discovered

A

cAMP

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2
Q

what are the types of signaling

A

juxtacrine (contact-dependent)
autocrine (act upon self)
paracrine (signal in immediate surroundings)
endocrine (signal in bloodstream, far away)
synaptic (NTs, neuron-neuron or neuron-cell)

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3
Q

what is an example of diff responses to the same ligand

A

Acetylcholine
in heart, acts on muscarinic receptor, slows HR
in salivary gland, acts on muscarinic receptor, causes secretion
on skeletal muscles, acts on a diff receptor, causes contraction

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4
Q

main diff between extra and intracellular ligands

A

extra - hydrophilic
intra - hydrophobic (and small)

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5
Q

explain amplification

A

each binding event can trigger multiple downstream molecules, allowing for exponential propagation of the signal
also allows for better regulation than a 1:1:1 reaction

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6
Q

relative speeds of signaling mechanisms:
channels, catalytic, G-protein, nuclear

A

channel: milliseconds
catalytic: seconds/mins
G-protein: seconds/mins
nuclear: hours (receptor triggers DNA transcription

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7
Q

where do steroid hormone receptors bind?

A

the LBD region of the receptor, inhibiting the inhibitor, then the signal is translocated to the response element on the DNA inside the nucleus

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8
Q

what does the coactivator do in the steroid hormone receptor?

A

binds to the ligand receptor, allowing for conformational changes that allow for transcription of the target gene

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9
Q

explain the diffusible messenger molecule of NO

A

when acetylcholine is taken up by the GPCR on endothelial cells, it is converted to Phospholipase C –> IP3 –> Ca/calmodulin –> NO synthase –> NO is released onto muscle cells leading to relaxation of the muscle cell

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10
Q

what type of structure do G proteins have

A

heterotrimeric (G-alpha, -beta, and -gamma)
on in the presence of GTP off in GDP
7 transmembrane regions

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11
Q

protein kinase vs phosphatase

A

kinase: phosphorylates protein
phosphatase: dephosphorylates protein

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12
Q

what are the ways in which a signaling complex is formed?

A

preformed (already held together by scaffolding before, activated in presence of ligand)
assembly (recruited after ligand binds receptor)

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13
Q

what are phosphoinositides

A

bound to membrane, can mind intracellular proteins that will hyperphosphorylate them and lead to downstream effects

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14
Q

what does GEF do

A

promotes dissociation of GDP, allowing for GDP/GTP exchange (does not phosphorylate, just causes GDP to dissociate and there is a higher conc of GTP in cell)

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15
Q

what is an example of a GEF

A

Sos

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16
Q

where does Sos/GEF bind?

A

SH3 domains on GRB2

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17
Q

where does GRB2 bind the EGF dimer

A

SH2 domain

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18
Q

agonist vs antagonist

A

agonist binds receptor, eliciting a similar response to ligand bind receptor
antagonist binds receptor in same or diff spot, inhibiting receptor

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19
Q

why was it so hard to study signal transduction

A

there are so many molecules it was impossible to know which were interacting. needed better purification methods

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20
Q

which subunit of GPCRs bind the GTP

A

alpha

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21
Q

what are the effects of GPCRs?

A

enzymes: adenylate cyclase, phospholipase C (PLC), phosphodiesterase (PDE)
ion channels: potassium (GIRK) and calcium (VDCC)

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22
Q

what are the regulators of GPCR signaling

A

aka RGS (regulators of GPCR signaling)
GAPs (GTPase activating proteins)

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23
Q

what do GAPs do

A

enhance inactivation
promote signals

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24
Q

what do GRKs do

A

GPCR kinases
phosphorylate agonist bound receptor
have seven genes

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25
Q

what do arrestins do

A

uncouple receptors form G-preteins, “arrest” signal
act as scaffolding, link GPCRs to other pathways (MAPK, NFkB)

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26
Q

what explains the different families of GPCRs and what features do they have

A

convergent evolution
7 TMs, conserved regions/domains
include the Rhodopsin, secretin/adhesion, and metabotropic families

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27
Q

key features of the 7TM GPCRs

A

N terminus = outside
C terminus = inside
N-linked glycosylation = sugar modification
Cys residues outside = disulfide bonds, stabilize TM domains
Cys residues inside = palmitoylation, anchor C-term to membrane
Ser/Thr = inside, kinase
phosphorylation sites

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28
Q

where are the most highly conserved areas of a GPCR

A

the 7TM regions

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29
Q

how can GPCRs be activated

A

protease/cleavage
glycoprotein hormones
neurotransmitters
all maintain the same basic shape and 7TM regions

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30
Q

what is rhodopsin

A

GPCR
associated with light intake in the retinas
7TMs form a pocket though which photons can pass through
opens pocket when activated

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31
Q

agonist and antagonists effects

A

neutral antagonists keep signal at basal level
inverse agonists dec basal level
partial agonists inc receptor response, but less than natural ligand
full agonist completely mimics response as if it were a natural ligand

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32
Q

G protein cycle

A

1) resting G-alpha/GDP, beta, and gamma all bound together
2) ligand binds receptor
3) receptor activates and GDP dissociation from alpha
4) GTP binds alpha
5) G-alpha/GTP dissociates from beta/gamma
6) GTP hydrolysis (returns alpha/GTP back to alpha/GDP, which reassociates with beta/gamma)

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33
Q

which steps are irreversible in the g protein cycle

A

alpha/GTP dissociation from beta/gamma
pushes cycle forward

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34
Q

types of G protein subunits

A

alpha, beta, and gamma
there are many types of ea (many alpha, many beta, many gamma), but you need at least one of each to make a full g protein
not all types work with ea other

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35
Q

key features of G-alpha

A

GTP binding domain
N terminus palmitoylation or myristoylation (binds membrane)

36
Q

key features of G-beta

A

unstable without gamma, forms very tight bond

37
Q

key features of G-gamma

A

stabilizes beta
C terminus isoprenylation (binds membrane)

38
Q

which G protein subunit binds receptor

A

alpha

39
Q

what do most isoforms of adenylate cyclases have

A

TM domains (9/10 isoforms have them)

40
Q

structure of adenylate cyclase

A

12 TM domains (2 repeats, ea with 6 parts)
C1 and C2 in cytoplasm allows for catalytic activity

41
Q

what is the classical GPCR pathway

A

activated GPCR > activated G-alpha activates adenylyl cyclase > adenylyl cyclase forms cyclic AMP > cAMP activates PKA > PKA is recruited into the nucleus > PKA activates CREB > CREB binds CBP (CREB binding protein) > CREB/CBP binds the CRE (cAMP response element) on DNA > transcription

42
Q

what are the mechanisms downstream of cAMP

A

PKA (classical)
cyclic nucleotide-gated ion channels
Epac (exchange proteins activated by cAMP)

43
Q

what are the second messengers of Phospholipase C (PLC)

A

DAG and IP3
PLC cleaves PIP2 into IP3 and DAG

44
Q

what does DAG do

A

activates PKC

45
Q

what does IP3 do

A

release Ca from the ER

46
Q

GPCR PLC pathway

A

GPCR activated > G-alpha gains GTP > G-alpha activates PLC > PLC cleaves PIP2 into IP3 and DAG > IP3 opens ion channel on ER, releasing Ca > DAG binds PKC, PKC binds Ca > PKC is activated

47
Q

what domains do RGS proteins have

A

RGS box
localization and protein interaction domains

48
Q

what do RGS proteins do

A

dephosphorylate GTP back to GDP (pushes pathway forward)
when bound to RhoGEF, promotes exchange of RhoGDP for RhoGTP on RhoGEF (downstream cytoskeleton effects), still the G-alpha is having GTP turned to GDP

49
Q

what associates with arrestins

A

GRKs

50
Q

what do GRKs do

A

after ligand has bound GPCR, facilitates binding of arrestin (stops response)
arrestins can also act as scaffold for other proteins that can lead to alternative pathways

51
Q

what is desensitization

A

GRK-arrestin mediated inhibition of GPCR signaling
causes endocytosis of GPCR

52
Q

what is the GRK pathway

A

GRK phosphorylates ligand bound receptor > recruits arrestin > arrestin binds, recruits AP2, ERK, and clathrin > receptor is endocytosed

53
Q

what molecules does arrestin recruit

A

AP2, ERK, clathrin

54
Q

what are the downstream effects of arrestin bound GPCRs

A

desensitization
internalization
scaffold for other pathways
Ubiquitination

55
Q

what are the implications of Arr1 and Arr2

A

more regulation, some have opposing effects in diff arrestin pathways

56
Q

what do biased agonists do

A

promote conformational changes in receptors that prefer activation of specific signaling pathways (one ligand favors a specific pathway)

57
Q

what are the pharma implications fo biased agonists

A

they are more specific and favor one GPCR pathway, limit off target effects

58
Q

themes of tyrosine kinase signaling

A

conversion of an extracellular signal to changes in intracellular tyrosine phosphorylation.
movement of signaling molecules to the membrane.
induces protein-protein interactions through specialized protein motifs.

59
Q

what is a non receptor TK

A

a TK without TM regions

60
Q

features of Src

A

first discovered in viruses (v-Src), human (c-Src) has high homology, first TK discovered
nonreceptor TK

61
Q

key domains of Src

A

kinase (SH1), SH2, SH3, unique domain (SH4)
2 phosphorylation sites (both tyrosines)
myristolation, palmitolation, autophosphorylation

62
Q

what is the diff between the two phosphorylation sites on Src

A

Tyr 416 (on kinase/SH1/activation loop) turns on Src
Tyr 527 (on C terminal tail) turns off Src

63
Q

how does Src become membrane associated

A

originally hydrophobic, post translational modifications:
cleavage of methionine (1st aa, now starts with glycine), myrisolation of that glycine, can have palmiltoyltion

64
Q

describe inactive Src

A

SH3 binds proline rich region
SH2 binds inhibitory P on C terminus, activation loop is blocked
phosphorylation of inactive site, dephosphorylation of active site

65
Q

describe active Src

A

SH2 releases inhibitory P, SH2 binds to RTK
fully active when active when kinase Tyr is autophosphorylated
phosphorylation of active site, desphosphorylation of inactive site

66
Q

what are the diff types of interactions in active vs inactive Src

A

active = intermolecular (SH2 binding RTK)
inactive = intramolecular (SH3 with proline rich region, SH2 with inhibitory P-Tyr)

67
Q

what is Csk and how does it work

A

tumor suppressor gene that is able to phosphorylate the inhibitory P on Src, dec cell proliferation

68
Q

key features of RTKs

A

TM proteins with ligand binding outside and kinase inside
dimerization and cross phosphorylation
numerous downstream pathways (transactivation)
regulate their own inactivation through Cbl

69
Q

general steps in RTK activation

A

1) Ligand-induced conformational change transmitted from the extracellular to intracellular domain
2) Tyrosine phosphorylation (cross-phosphorylation) of C-terminal tyrosine residues (or phosphorylation of a scaffold; e.g. IRS1, GAB14,..)
3) “Relaxation” of the “activation loop” to allow access to the active site
4) Further tyrosine phosphorylation of the C-terminal domain to provide docking sites for SH2 and PTB domain-containing proteins

70
Q

what are the common domains in Src, PLC, and Grb2

A

SH2 and SH3

71
Q

what is the main difference in PTB domain and SH2 domain binding

A

SH2 ligand binds in pocket
PTB ligand augments beta sheet

72
Q

what do SH2 domains bind

A

tyrosine-phosphorylated sequences

73
Q

what do SH3 domains bind

A

proline rich regions

74
Q

what does the PH domain bind

A

PIP3

75
Q

what is IRS and what does it bind

A

insulin receptor subunit
acts as an adapter protein to mediate signaling
PH domain binds PTB, which binds PIP3 and other SH2 domain proteins

76
Q

SH2 domain proteins

A

PIP3, Grb2

77
Q

what does Cbl do

A

E3 Ub ligase
after EGFR is autophosphorylated, Tyr phosphorylation triggers Ub, gets degraded after being internalized

78
Q

PI3K/Akt pathway overview

A

RTK phosphorylates PI3K > PI3K phosphorulates PIP2, converting it to PIP3 > PIP3 binds PH domains, can act on both PDK1 and Akt/PKB > PIP3 recruits both Akt and PDK1 allowing them to interact > PDK1 phosphorylates Akt > Akt phosphorylates other downstream proteins > affect survival, proliferation, and motility

79
Q

what is an inosital ring

A

head group that is inserted into the membrane
ex: PIP2, PIP3

80
Q

what converts PIP2 to PIP3

A

PI3K

81
Q

what converts PIP3 to PIP2

A

PTEN

82
Q

what are the important domains in p110

A

Adapter binding, Ras binding, C2, Helical, Kinase

83
Q

what are the importnat domains in p85

A

SH3, Rho-GAP, nSH2, cSH2

84
Q

what does p85 bind

A

PI3K at the PH domain
if it is insulin, p85 binds IRS instead of directly to PI3K
also binds p110, which in turn can bind Ras

85
Q

where does PIP bind PLC

A

PH domain

86
Q
A

Core course (2 decks)

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