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PDA Block 1 > Signal Transduction > Flashcards

Signal Transduction Flashcards

1
Q

Why is Signal Transduction important?

A

In a multicellular organism, cells need to respond to signals in order to communicate with each other

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2
Q

How do cells receive and respond to signals?

A

Cells receive signals by interacting with cellular signaling molecules which transduce the signal and induce a response to the signal

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3
Q

Signaling by secreted molecules (4 types)

A
  1. Paracrine signaling: Local mediators are secreted by the signaling cell and received by surrounding target cells
  2. Autocrine signaling: mediators are secreted and received by the same cell
  3. Synaptic signaling: Neurotransmitters are secreted by the pre-synaptic cleft and are received by the post synaptic cell
  4. Endocrine signaling: Hormones are secreted into the blood stream
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4
Q

Signaling by plasma membrane bound molecules

A

Signaling molecule is a transmembrane protein

Target cell in direct contact with signaling cell

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5
Q

Two major unique characteristics of intracellular steroid receptors

A
  1. These receptors are intracellular, and interact with their ligand in either the cytoplasm or nucleus
  2. These receptors are ligand-activated transcription factors
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6
Q

Carrier protein for cortisol

A

Corticosteroid-binding globulin (CBG)

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7
Q

Three parts of a steroid receptor

A

1) Hormone binding site
2) DNA binding domain
3) Transcription-activating domain

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8
Q

In the basal state, GR receptors are found in the _______

Thyroid and retinoid receptors are found in the _______

A

Ctyoplasm; Nucleus

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9
Q

GRE (Glucocorticoid-response element)

A

glucocorticoid response element - A DNA sequence that binds steroid receptors

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10
Q

GR (Glucocorticoid receptor) in basal state

A

Exists as an inactive complex in the cytosol associated with HSP90 and other cytosolic (inhibitory) proteins

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11
Q

Membrane Receptors

A

Ion Channel-Linked Receptor
G-Protein Coupled Receptor
Enzyme Linked Receptor

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12
Q

Receptors for acetylcholine, GABA, serotonin, and glycine have __ subunits, and receptors for glutamate have __ subunits

A

5;4

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13
Q

Nicotinic Acetylcholine Receptor = the first ion channel to:

A

1) Be purified
2) Have its sequence determined
3) Be reconstituted in a lipid bilayer
4) Provide a single channel recording

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14
Q

Nicotinic Acetylcholine Receptor Function

A

Consists of 5 subunits

Binding of ACh to the α subunits opens the channel causing influx of cations

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15
Q

Location of Nicotinic Acetylcholine Receptors

A

Neuromuscular Junction
Peripheral autonomic nervous system
Central Nervous system

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16
Q

GABA Receptor-Gated Cl- channels

A

Primary postsynaptic inhibitory transmitter in CNS

GABA binds receptor → CL- channels open → Influx of CL- into cell → Hyperpolarization and inhibitory response

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17
Q

G-protein coupled receptor passes through the plasma membrane ______ times

A

7

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18
Q

3 Parts of G-protein coupled receptor

A

Receptor provides specificity
Herterotrimeric G protein is the transducer (GTP-bound and GDP-bound states)
Effector provides the catalytic component to generate the second messenger

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19
Q

Heterotrimeric G Proteins

A

Three types of subunits (α,β, and γ) which function as a dimer
Gα: binds GTP and interacts with effectors (Hydrolyzes GTP→ GDP)
Gβγ: inhibits Gα; anchors to membrane

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20
Q

Different Gα subunits:

A

Gαs (stimulates adenylyl cyclase)
Gαi (inhibits adenylyl cyclase)
Gαq (activates phospholipase C)

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21
Q

Enzyme Linked Receptors

A

Tyrosine Kinase-Linked
Serine/threonine kinase-linked
Protein phosphatase-linked
Guanylyl cyclase-linked

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22
Q

Tyrosine Kinase-Linked Receptors

A

EGF (Epidermal growth factor) Receptor: Inactive is monomer; active is dimer
PDGF (Platelet-derived growth factor) Receptor: Inactive is monomer; active is dimer
Insuling Receptor: Inactive is dimer, active is tetramer

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23
Q

EGF Receptor: Ligand binding causes…

A

Dimerization
Activation of cross autophosphorylation
Binding of intracellular signaling molecules

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24
Q

4 classes of major receptors that are major drug targets

A
  1. Intracellular steroid receptors
  2. Ion Channel-linked receptors
  3. G Protein-coupled receptors
  4. Enzyme linked receptors
25
Q

Transcription factors (CREB)

A

Proteins that bind DNA and regulate (either promote or inhibit) the transcription of genes

26
Q

Activated transcription factors induce transcription by activating __________

A

RNA polymerase

27
Q

Protein Kinases

A

Catalyze the addition of a phosphate group to the side chain of amino acids in proteins and peptides

28
Q

Serine/threonine-specific protein kinases

A

PKA, PKC, Ca(2+)/calmodulin-dependent kinase, MAP kinase (such as ERK, JNK, or p38 kinase)

29
Q

Tyrosine-specific protein kinases

A

Tyrosine kinase-linked receptors (e.g. EGF receptor) and cytoplasmic kinases such as Src and Abl

30
Q

Dual specificity kinases

A

Can phosphorylate both threonine and tyrosine: Map kinases kinases (MKK1)

31
Q

Protein phosphatases

A

Catalyze the cleavage of a phosphate group from the side chain of amino acids in proteins and peptides (less variety than protein kinases)

32
Q

How are the activities of protein kinases and protein phosphatases regulated

A

Second messengers

33
Q

Second messengers

A

Small, diffusable molecules that are generated in response to ligand-receptor interactions and activate downstream effectors

34
Q

Cyclic adenosine monophosphate (cAMP)

A

Generation: when Gαs activates adenylyl cyclase (activated adenylyl cyclase converts ATP to cAMP)
Effector: cAMP activates Protein Kinase A

35
Q

Diacylglycerol (DAG) and Inositol Triphosphate (IP3)

A

Generation: made when Gαq activates phospholipase C (PLC) - cleaves PIP2 to DAG and IP3
Effectors: DAG activates PKC; IP3 binds to IP3 receptors of ER - releases calcium

36
Q

Ca(2+)

A

Generation: Generated by opening of ion channels
Effectors: Binds to proteins and activates PKC and other kinases and enzymes

37
Q

cAMP pathway

A

1) Binding of ligand to GPCR activates Gαs
2) Active Gαs-GTP binds to adenylyl cyclase and activates it
3) Each activated adenylyl cyclase generates many cAMP molecules from ATP
4) cAMP molecules activate protein kinase A (PKA)
5) Each activated PKA can phophorylate and activate many copies of substrate X
6) Each copy of Substrate X may activate many copies of the next downstream substrate

38
Q

How is PKA activated

A

cAMP binds to regulatory subunits and releases catalytic subunits

39
Q

GPCRs coupled to Gαq regulate the ______-______ pathway

A

Inositol-lipid

40
Q

Inositol-lipid pathway

A

1) Ligand activates a GPCR
2) Gαq is activated by binding GTP
3) PLC is activated by binding Gαq-GTP
4) Active PLC cleaves PIP2 into IP3 and DAG
5) IP3 diffuses into the cytoplasm and causes Ca (2+) release from ER
6) DAG remains in the membrane and activated PKC
7) Ca(2+) binds to calmodulin and activates Ca(2+)/calmodulin dependent kinase

41
Q

Monomeric G proteins

A

Activated by interacting with proteins known as “guanine nucleotide exchange factors” (GEFs)
Inactivated by interacting with proteins known as “GTPase activating proteins” (GAPs)

42
Q

Difference between heterotrimeric and monomeric G proteins

A

1) Heterotrimeric G proteins (Gα subunit) are activated by direct interaction with a GPCR (EGFR)
2) Monomeric G proteins (such as Ras) are activated by direct interaction with a GEF (SOS)

43
Q

GEFs are activated when they are recruited to activated tyrosine kinase-linked receptors by _______ ________

A

Adaptor proteins (GRB2)

44
Q

Activation Cycle of Ras (and other monomeric G Proteins)

A

1) Ras interacts with a GEF, which causes Ras-GDP to release its bound GDP and bind GTP, resulting in formation of active Ras-GTP
2) Active Ras-GTP binds and signals to other molecules
3) Ras has intrinsic GTPase activity and hydrolyzes bound GTP to GDP
4) Upon association with GAP, Ras-GTP hydrolyzes to inactive Ras-GDP
5) Ras-GDP is inactive until a new signal causes it to associated with a GEF

45
Q

Ras-GTP activates the ____ ______ signaling cascade

A

MAP kinase

46
Q

MAP kinase signaling cascade

A

Ras-GTP activates Raf (MKKK)
Raf phophorylates MKK1
MKK1 phosphoylates ERK (MAP kinase)
ERK phophorylates many different transcription factors

47
Q

Gefitinib and Erlotinib

A

Drugs that target the kinase domain of the EGF receptor and inhibit signaling by the EGF receptor

48
Q

Gefitinib and Erlotinib decrease lung tumor burden in ___ of patiens who have mutated EGF receptor
These drugs are effective in only ___ of patients w/o receptor mutations

A

80%; 10%

49
Q

EGF receptor mutations occur more frequently in

A

Female patients of Asian descent who have never smoked

50
Q

Attenutation of signaling is accomplished by:

A

Ligand inactivation or dissociation from the receptor
Receptors dissociate from other proteins
Adaptor protein complexes dissociate
G-proteins hydrolyze GTP to the GDP inactive state
Phophorylated proteins are de-phophorylated
Second messengers are metabolized or diffuse away
Ions are sequestered or pumped out

51
Q

Adaptation

A

Receptor-mediated endocytosis

Occurs when signaling system responds to the intensity and frequency of stimulation

52
Q

Coated-pits (formed by clathrin)

A

Specialized inward-curved membranes where receptor-mediated endocytosis occurs

53
Q

CURL

A

Compartment of Uncoupling of Receptor and Ligand (these vesicles have low pH (4.5-5) to favor dissociation of ligand)

54
Q

Retroendocytosis

A

Dissociated ligands incorporate into vesicles and are recycled

55
Q

Homologous desensitization

A

Signaling by the receptor is attenuated - can occur due to covalent modification of the ligand-bound receptor

56
Q

What two molecules work together to desensitize GPCR

A

phosphorylation by β-adreneregic kinase (βark) followed by binding of β-arrestin to phosphorylated receptor

57
Q

How is GCPR desensitized by PKA

A

Stimulated receptor activates PKA, the activated PKA can phosphorylate the receptor and desensitize it

58
Q

Heterologous desensitization

A

Signaling by both the stimulated receptor and by other different types of receptors is attenuated:
Both stimulated and unstimulated receptors are blocked

PDA Block 1 (13 decks)

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