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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
what do arrestins do
uncouple receptors form G-preteins, "arrest" signal act as scaffolding, link GPCRs to other pathways (MAPK, NFkB)
26
what explains the different families of GPCRs and what features do they have
convergent evolution 7 TMs, conserved regions/domains include the Rhodopsin, secretin/adhesion, and metabotropic families
27
key features of the 7TM GPCRs
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
28
where are the most highly conserved areas of a GPCR
the 7TM regions
29
how can GPCRs be activated
protease/cleavage glycoprotein hormones neurotransmitters all maintain the same basic shape and 7TM regions
30
what is rhodopsin
GPCR associated with light intake in the retinas 7TMs form a pocket though which photons can pass through opens pocket when activated
31
agonist and antagonists effects
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
32
G protein cycle
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)
33
which steps are irreversible in the g protein cycle
alpha/GTP dissociation from beta/gamma pushes cycle forward
34
types of G protein subunits
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
35
key features of G-alpha
GTP binding domain N terminus palmitoylation or myristoylation (binds membrane)
36
key features of G-beta
unstable without gamma, forms very tight bond
37
key features of G-gamma
stabilizes beta C terminus isoprenylation (binds membrane)
38
which G protein subunit binds receptor
alpha
39
what do most isoforms of adenylate cyclases have
TM domains (9/10 isoforms have them)
40
structure of adenylate cyclase
12 TM domains (2 repeats, ea with 6 parts) C1 and C2 in cytoplasm allows for catalytic activity
41
what is the classical GPCR pathway
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
what are the mechanisms downstream of cAMP
PKA (classical) cyclic nucleotide-gated ion channels Epac (exchange proteins activated by cAMP)
43
what are the second messengers of Phospholipase C (PLC)
DAG and IP3 PLC cleaves PIP2 into IP3 and DAG
44
what does DAG do
activates PKC
45
what does IP3 do
release Ca from the ER
46
GPCR PLC pathway
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
what domains do RGS proteins have
RGS box localization and protein interaction domains
48
what do RGS proteins do
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
what associates with arrestins
GRKs
50
what do GRKs do
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
what is desensitization
GRK-arrestin mediated inhibition of GPCR signaling causes endocytosis of GPCR
52
what is the GRK pathway
GRK phosphorylates ligand bound receptor > recruits arrestin > arrestin binds, recruits AP2, ERK, and clathrin > receptor is endocytosed
53
what molecules does arrestin recruit
AP2, ERK, clathrin
54
what are the downstream effects of arrestin bound GPCRs
desensitization internalization scaffold for other pathways Ubiquitination
55
what are the implications of Arr1 and Arr2
more regulation, some have opposing effects in diff arrestin pathways
56
what do biased agonists do
promote conformational changes in receptors that prefer activation of specific signaling pathways (one ligand favors a specific pathway)
57
what are the pharma implications fo biased agonists
they are more specific and favor one GPCR pathway, limit off target effects
58
themes of tyrosine kinase signaling
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
what is a non receptor TK
a TK without TM regions
60
features of Src
first discovered in viruses (v-Src), human (c-Src) has high homology, first TK discovered nonreceptor TK
61
key domains of Src
kinase (SH1), SH2, SH3, unique domain (SH4) 2 phosphorylation sites (both tyrosines) myristolation, palmitolation, autophosphorylation
62
what is the diff between the two phosphorylation sites on Src
Tyr 416 (on kinase/SH1/activation loop) turns on Src Tyr 527 (on C terminal tail) turns off Src
63
how does Src become membrane associated
originally hydrophobic, post translational modifications: cleavage of methionine (1st aa, now starts with glycine), myrisolation of that glycine, can have palmiltoyltion
64
describe inactive Src
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
describe active Src
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
what are the diff types of interactions in active vs inactive Src
active = intermolecular (SH2 binding RTK) inactive = intramolecular (SH3 with proline rich region, SH2 with inhibitory P-Tyr)
67
what is Csk and how does it work
tumor suppressor gene that is able to phosphorylate the inhibitory P on Src, dec cell proliferation
68
key features of RTKs
TM proteins with ligand binding outside and kinase inside dimerization and cross phosphorylation numerous downstream pathways (transactivation) regulate their own inactivation through Cbl
69
general steps in RTK activation
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
what are the common domains in Src, PLC, and Grb2
SH2 and SH3
71
what is the main difference in PTB domain and SH2 domain binding
SH2 ligand binds in pocket PTB ligand augments beta sheet
72
what do SH2 domains bind
tyrosine-phosphorylated sequences
73
what do SH3 domains bind
proline rich regions
74
what does the PH domain bind
PIP3
75
what is IRS and what does it bind
insulin receptor subunit acts as an adapter protein to mediate signaling PH domain binds PTB, which binds PIP3 and other SH2 domain proteins
76
SH2 domain proteins
PIP3, Grb2
77
what does Cbl do
E3 Ub ligase after EGFR is autophosphorylated, Tyr phosphorylation triggers Ub, gets degraded after being internalized
78
PI3K/Akt pathway overview
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
what is an inosital ring
head group that is inserted into the membrane ex: PIP2, PIP3
80
what converts PIP2 to PIP3
PI3K
81
what converts PIP3 to PIP2
PTEN
82
what are the important domains in p110
Adapter binding, Ras binding, C2, Helical, Kinase
83
what are the importnat domains in p85
SH3, Rho-GAP, nSH2, cSH2
84
what does p85 bind
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
where does PIP bind PLC
PH domain
86

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