Lecture 11: Signal Transduction II: Receptors Flashcards

1
Q
A
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2
Q

signal receptors

A

-7TM
-GPCR
-LGIC
-kinases

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3
Q

Ligand-gated ion channels (LGIC)

A

-2 domains
-involved in neuronal signaling

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4
Q

LGIC mechanism

A

-first messenger (ligand) binds the channel receptor
-channel opens (gating) to allow ions to cross membrane

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5
Q

ions

A

Na+, K+ Ca2+

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6
Q

LGIC extracelllular domain

A

binds first messenger

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7
Q

LGIC transmembrane domain

A

pore through which ions flow

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8
Q

LGIC in neuronal signaling

A

-neurotransmitter ligands released from presynaptic neuron into synaptic cleft
-NT binds to channel, induces ion flow
-leads to quick post synaptic signal by changing the potential across the membrane

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9
Q

LGIC first messengers

A

-serotonin
-y-aminobutyric acid (GABA)
-nicotinic acetylcholine
-glutamate
-glycine

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10
Q

LGIC clinical relevance

A

-site at which anaesthetic agents act
-involved in BP regulation and cardiovascular disease

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11
Q

Nicotinic acetylcholine receptor

A

-Gating: binding to extracellular LBD triggers structural change to widen channel
-opening: sodium ions flow through open channel down gradient into cells
-depolarize post-synaptic membrane

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12
Q

Receptor tyrosine kinases

A

-ligands bind EC domains
-induce dimerization of receptor
-activates IC activity of receptor
-activated cytoplasmic domain phosphorylate on tyrosine to form specific binding sites
-leads to phosphorylation of other proteins
-termination by internalization with ligand dissociation and degradation

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13
Q

kinases examples

A

-insulin receptor
-growth factor receptors (epidermal, platelet-derived)

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14
Q

Kinase receptors

A

-many families
-various EC domains
-cell growth
-dysfunction=cancer

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15
Q

Besides receptor internalization, another way to terminate the signaling from receptor tyrosine kinases could be:

A

protein phosphatase as part of a protein phosphorylation cycle

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16
Q

Ras/MAP kinase signal cascade

A

-growth factor receptor binds growth factor ligand and initiates mitogen-activated protein kinase (MAP kinase) cascade

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17
Q

Ras/MAP kinase signal cascade mech

A

-activated Ras binds and activates MAP3K which triggers cascade
-SLIDE 9-10 pic

18
Q

Activation of G-protein Ras

A

-molecular switch to activate cell proliferation, migration, transformation, survival
-signal activation involves: adaptor protein (Grb2) and GEF (Sos)

19
Q

Ras mutations

A

-permanent activation of Ras enzyme
-big in pancreatic cancer
-HRas, KRas, NRas
-meds lacking

20
Q

Activated Ras effectors

A

-PLCe
-RalGDS
-Raf
-PI3K

-so many and so many pathways = very problematic

21
Q

KRAS structure

A

-hypervariable region (HVR)
-G domain
-active when GTP bound
-inactive when GDP bound

22
Q

hypervariable region

A

-localization to membrane

23
Q

G-domain

A

-switch I and II
-P-loop
-slide 12 pic

24
Q

activation of KRAS

A

when GTP bound

25
inactivation of KRAS
when GDP bound
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Ras
-membrane bound -monomeric G protein -activated by GF or by T cell receptors
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P loop
changes here cause most cancer
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Switch
-conformation of 2 loops based on GTP or GDP bound
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Active Ras
-GTP bound -binds specific effectors -activates multiple pathways
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Hydrolysis of GTP to GDP
-GTP to GDP -rate increased by GTPase-activating proteins (GAP)
31
Guanine nucleotide exchange factors (GEF)
-increase GDP dissociation -slow hydrolysis -prolong activation of Ras -promotes cancer
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Slide 14
slide 14
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Mutations KRAS
-single-base missense mutations in KRAS -many in P-loop -site varies based on cancer type -decrease GTPase activity -increase affinity for GTP -KRAS always active = cancer
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KRAS inhibition
-very difficult -very high affinity for GTP and GDP -mutant structure binds GTP with increased affinity -constitutively active
35
Target G12C KRAS mutant
-irreversible inhibitor -allosteric pocket in switch II -lead compound that covalently links to C12 -covalently bound inhibitor prevents GTP binding
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G-protein-coupled receptors (GPCRs)
-1000 different in human genome -most common target of pharmaceuticals -many hormone and NT receptors -structural similarity -signal via proteins -no enzyme activity -no scaffolding
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GPCR structure
-7 a-helical transmembrane regions -conformational change upon receiving signal
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G-protein cycle (trimeric G protein)
-release of GDP is slow -transient association w an agonist bound GCPR increases GDP release from Ga =GEF activity -one agonist bound GPCR can activate 10-100 G proteins =BIG amplification -intrinsic GTPase activity converts on to off form -sometimes facilitated by regulators of G-protein signaling, RGS proteins
39
Desensitization
phosphorylation of GPCR residues in THIS region by kinase SLIDE 19
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SLIDE 19
SLIDE 19
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Heterotrimeric G-proteins that couple to GPCRs
-3 subunits Ga, GB, Gy -association with agonist-bound GPCR induces dissociation of GDP and GTP binding
42
Ga
-GTPase activity -20 subtypes -dissociates from By complex and stimulates/represses effector protein when activated