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Biochem 3 > Signal Transduction > Flashcards

Signal Transduction Flashcards

1
Q

Juxtacrine mode

A

direct contact

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2
Q

juxtacrine signal

A
  • membrane bound surface proteins (surface protein/receptor interaction)
  • transmembrane protein channels (gap junction: docking connexons)
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3
Q

juxtacrine target

A

adjacent cells

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4
Q

endocrine mode

A

secreted molecules

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5
Q

endocrine signal

A

hormones

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6
Q

endocrine binding affinity

A

very high

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7
Q

endocrine range

A

long

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8
Q

endocrine target

A

distant cells

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9
Q

paracrine mode

A

secreted molecules

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10
Q

paracrine signal

A

local mediators/large proteins (growth factors, cytokines)

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11
Q

paracrine binding affinity

A

low to high

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12
Q

paracrine range

A

short

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13
Q

paracrine target

A

neighboring cells

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14
Q

synaptic mode

A

secreted molecules

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15
Q

synaptic signal

A

neurotransmitters

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16
Q

synaptic binding affinity

A

very low

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17
Q

synaptic range

A

very short

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18
Q

synaptic target

A

postsynaptic cells

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19
Q

autocrine mode

A

secreted molecules

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20
Q

autocrine signal

A

local mediators/large proteins (growth factors, cytokines)

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21
Q

autocrine binding affinity

A

low to high

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22
Q

autocrine range

A

short

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23
Q

autocrine target

A

same cell

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24
Q

3 aspects of signal transduction

A

selective response, amplification system, coordination of handling numerous signals

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25
Q

crosstalk

A

component from one pathway interacts/influences a component of another pathway

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26
Q

4 signal characteristics

A

specificity, relatively small molecules employed for signal, rapid deployment, can be turned off (often rapidly)

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27
Q

on demand vs pre made signal

A

on demand: intracellular signal is made when extracellular signal arrives

pre-made: intracellular signal stored in vesicles, vesicles released when extracellular signal arrives

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28
Q

Ways to turn off signal

A
  • decreased concentration of first messenger
  • receptor desensitization (inactivation via structural modification like phosphorylation; down-regulation via receptor internalization and degredation which is more common)
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29
Q

connexon

A
  • 4 transmembrane domains, 2 extracellular loops (3 cysteines/loop)
  • connect two cells via gap junctions
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30
Q

endocrine on/off response time

A

slow (minutes to hours) because of tight binding and time required to decrease blood concentration

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31
Q

paracrine on/off response time

A

rapid

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32
Q

synaptic on/off response time

A

very rapid (milliseconds)

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33
Q

autocrine on/off response time

A

rapid

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34
Q

neurotransmitters system

A

synaptic

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35
Q

neurotransmitters physical characteristics

A

hydrophillic molecules, very small <1kDa, fast diffusion

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36
Q

hormones system

A

endocrine

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37
Q

hormones physical characteristics

A

-hydrophillic, small, <5kDa, usually charged
OR
-hydrophobic, very small, <1kDa, membrane permeable

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38
Q

growth factors system

A

paracrine, autocrine

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39
Q

growth factors physical characteristics

A

polypeptides (some multimers), small-large, 6-80kDa, local acting

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40
Q

cytokines system

A

paracrine, autocrine

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41
Q

cytokines physical characteristics

A

polypeptides, usually multimers, small to large, 8-70kDa

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42
Q

agonist vs antagonist

A

agonist: ligand that activates normal response (excitatory or inhibitory)
antagonist: ligand that induces no response (blocks normal response)

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43
Q

Coupling

A

intracellular protein that transmits the signal of an activated receptor to an effector protein

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44
Q

adaptor

A

intracellular protein that lacks intrinsic enzymatic activity but contains several domains that mediate protein-protein interactions

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45
Q

SH2 binding affinity

A

phosphorylated tyrosines

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46
Q

PTB binding affinity

A

phosphorylated tyrosines

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47
Q

SH3 binding affinity

A

prolines (-X-P-p-X-P-)

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48
Q

PH binding affinity

A

phosphorylated inositol phospholipids (in plasma membrane, inositol portion hangs into cytosol)

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49
Q

Protein phosphorylation

A

Phosphorylate–>via protein kinases that use ATP to replace hydroxyl group with phosphate group

Dephosphorylate-> via protein phosphatases that dephosphorylate via hydrolysis

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50
Q

Guanine nucleotide binding (g protein cycle)

ON

A

GDP exchanged for GTP

Assisted by activated receptor for trimeric G; guanine nucleotide exchange factors (GEFs) for monomeric G

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51
Q

Guanine nucleotide binding (g protein cycle)

OFF

A

Hydrolysis back to inactivated GDP form
Catalyzed by intrinsic GTPase for trimeric G; intrinsic GTPase with help from GTPase-activating proteins (GAPs) for monomeric G

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52
Q

Relationship of KD and binding affinity

A

small Kd=high binding affinity=low concentration

large KD=low binding affinity=high concentration

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53
Q

Intracellular receptor class

A
  • hydrophobic hormones enter through plasma membrane
  • bind to receptor (which is bound to HSP before)
  • receptor/ligand dimer enter nucleus and bind to DNA
  • direct
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54
Q

Cell surface receptor class

A

more common

  • hydrophillic hormones/NT/Growth factors/cytokines bind to cell surface receptor and cause conformational change
  • receptor affects second messangers
  • indirect
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55
Q

ligand gated ion channel

system

A

synaptic

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56
Q

ligand gated ion channel

ligands

A

neurotransmitters

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57
Q

ligand gated ion channel

binding

A

very low affinity
high KD
KD=10^-6 to 10^-3

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58
Q

ligand gated ion channel

examples

A

cation selective: excitatory (nicotinic ACh, glutamate)

anion selective: inhibitory (glycine, GABA)

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59
Q

ligand gated ion channel

structure

A

multimeric ring-like complex of 3-5 polypeptides with multiple transmembrane domains
opens internal water filled pore

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60
Q

ligand gated ion channel

termination

A

Rapid ligand removal by diffusion, enzymatic degredation, reuptake
Also can form inactive ligand-bound state via RECEPTOR INACTIVATION (inactive despite the fact ligand is bound, causes channel closing and NT release)

61
Q

G protein coupled receptor

system

A

synaptic, endocrine, paracrine, autocrine

62
Q

G protein coupled receptor

ligands

A

NT, hormones, cytokines (particularily chemokines)

63
Q

G protein coupled receptor

binding

A

intermediate range

KD=10^-9 to 10^-6M

64
Q

G protein coupled receptor

Examples

A

muscarinic ACh, beta adrenergic, rhodopsin

65
Q

G protein coupled receptor

structure

A

N terminous outside cell: site of glycosylation
7 transmembrane alpha helixes
c terminus inside cell, site of phosphorylation and g protein binding
large ligands bind to extracellular loops, small ligands bind in pocket (of rhodopsin receptor)

66
Q

G protein coupled receptor
heterotrimeric g proteins/coupling proteins
Structure

A

alpha subunit: largest, hydrophillic, covalent attachment to plasma membrane with lipid anchor, GDP/GTP binding site and GTPase activity, interact with effector proteins

beta-gamma complex: smaller dimer, hydophobic, covalently attached to plasma membrane with lipid anchor, some interaction with effector proteins

alpha has many different forms; beta gamma dimer similar for differ g protein subtypes

67
Q

G protein coupled receptor

Action

A
  • ligand binds and causes conformational change in receptor
  • recognition site exposed and g protein binding occurs (location of amplification)
  • GDP/GTP exchange and g protein dissociates
  • alpha subunit binds to enzyme (like adenylate cyclase) causing release of second messangers (Site of most amplification)
  • intrinsic GTPase activation, hydrolysis of GTP to GDP and release from enzyme
  • g protein reforms
68
Q

G protein coupled receptor

termination

A
  • extracellular enzymes inactivate ligands
  • receptor mediated endocytosis
  • receptor phosphorylation by protein kinases (MAJOR MECHANISM OF DESENSITIZATION): PKA phosphorylate with or without ligand bound, GPCR specific protein kinases (GRKs) phosphorylate only with bound ligand.
69
Q

Caffeinated alcohol drinks

A

alcohol keeps GABA ligand channel open longer alosterically, decreases membrane potential, increases neural supression, increase dopamine

caffeine blocks adenosine binding on g protein receptor (antagonist), cancels adenosines effect, allows increased neural activity, increases dopamine

70
Q

enzyme linked receptor

system

A

endocrine, paracrine

71
Q

enzyme linked receptor

ligands

A

hormones, growth factors

72
Q

enzyme linked receptor

binding

A

very high affinity

KD=10^-12 to 10^-9

73
Q

enzyme linked receptor

examples

A

receptor tyrosine kinase (RTK): EGF, insulin, and less important: FGF, PDGF
Receptor serine/threonine kinase: TGF-beta, and less important BMP

74
Q

enzyme linked receptor

structure

A

-subunits are single polypeptide chain with large extracellular N terminal domain for ligand binding, single transmembrane domain, intracellular c terminal domain with catalytic domains

75
Q

enzyme linked receptor

RTK structure/action

A
  • dimer
  • inactive RTK monomers in membrane
  • growth factor (ligand) binds to membrane receptor causing dimerization and activation of kinase domain
  • autophosphorylation (cross phosphorylation) of tyrosine residues in tyrosine kinase domain
  • SH2 and PTB domains bind to phosphorylated tyrosines, set up large signalling cascades (like MAP kinase cascade)
76
Q

Map kinase cascade

A

Mitogen activated protein kinase cascade; after RTK activation or cytokine receptor activation

  • adaptor protein binds it’s SH2 domain to phosphorylated tyrosine domain
  • SH3 domain of adaptor protein binds RAS-activating protein
  • RAS activating protein exchanges GDP for GTP on inactive RAS at membrane
  • Active RAS binds to N-terminal of MAPKKK (brings MAPKKK from cytoplasm to membrane)
  • MAPKKK activated, attracts MAPKK to membrane and phosphorylates serine/threonine using ATP
  • Activated MAPKK phosphorylates threonine/tyrosine of MAPK using ATP
  • Activated MAPK phosphorylates serine/threonine using ATP either in cytoplasm to change enzyme activity or nucleus to change gene expression
77
Q

Enzyme linked receptor

Serine/threonine kinase structure/action

A
  • tetramer
  • inactive type 1 and type 2 monomers in membrane
  • growth factors (ligand) bind to type 2 and dimerize with type 1, causing activation and cross phosphorylation of Ser/Thr of type 1
  • SMAD binds to and gets phosphorylated by receptor, unfolds and becomes active
  • SMAD dissociates from receptor, dimerizes with different SMAD subtype, NLS revealed and taken to nucleus where gene expression is altered
78
Q

Enzyme linked receptor

termination

A

Receptor mediated endocytosis

  • adaptin binds to intracellular sequence on ligand/receptor sequence, clatherin binds to adaptin
  • clatherin polymerizes and vacuole is formed
  • vacuole released into cytoplasm, clatherin coat shed, fused with endosome, ligand-receptor complexes dissociated
  • receptors either recycled to plasma membrane or transferred to lysosome for degredation
79
Q

Cytokine receptor

system

A

paracrine, autocrine

80
Q

cytokine receptor

ligands

A

cytokines, some growth factors

81
Q

cytokine receptor

binding

A

intermediate

KD=10^-9 to 10^-6M

82
Q

cytokine receptor

examples

A

Class I, interleukin (IL2 [through IL7 and IL9), dimers]
Class II, interferon (IFN-gamma, [IFN-alpha, IFN-beta, IL-10), multimers]
Tumor necrosis factor (TNF-alpha, [TNF-beta), trimers]

83
Q

cytokine receptor

structure

A
  • diverse structure
  • single polypeptide with large extracellular N-terminal domain for ligand binding, single transmembrane domain, intracellular c-terminal domain with different protein-protein interaction motifs but NO INTRINSIC ENZYMATIC ACTIVITY
  • multimeric complexes
84
Q

What differentiates structure of cytokine receptor and enzyme linked receptor?

A

intracellular C domain is catalytic in enzyme linked receptor but has no intrinsic enzymatic activity in cytokine receptor

85
Q

cytokine receptor

action

A
  • inactive monomeric receptors in membrane have associated JAKs on prolines
  • cytokine binds and causes receptor dimerization
  • JAK activated (via phosphorylation) and cross phosphorylation of tyrosine in subunits
  • STAT SH2 domains binds to phosphorylated tyrosines
  • JAK phosphorylate STAT, STAT activated
  • STATs dissociate from receptor and dimerize
  • STAT dimer translocated to nucleus to alter gene expression, or could start MAP kinase cascade
86
Q

cytokine receptor

termination

A
  • phosphatases remove tyrosine phosphates from receptor and/or active STAT
  • SOCS (supressor of cytokine signaling) proteins inhibit STAT phosphorylation by binding/inhibiting JAK or competing with STAT for receptor binding sites
  • endocytosis triggered by multimer formation
87
Q

Ebola virus

A
  • replaces STAT in import complex (importin-alpha5 adapter and Importin-beta receptor)
  • virus (VP24 protein) translocated to nucleus instead of STAT dimer
  • complex dissociates by Ran-GTP
  • antiviral response supressed
88
Q

Intracellular receptor structure

A
  • polypeptide dimer with DNA-binding domains

- binds as dimer to DNA sequence

89
Q

intracellular receptor examples

A

Progesterone, thyroxine, retinal

90
Q 
Ligand-gated ion channel
structure/action
Cation selective (nicotinic ach)
A

4 transmembrane domains, 2 intracellular loops
M3 transmembrane domain has large hydrophobic aa and small polar aa (ligand binding causes polar aa to face inside/open channel)
requires binding of 2 ligands to alpha subunits

91
Q

KD equation and units

A

KD=koff/kon=([L][R])/[LR]

Units are concentration

92
Q

Small KD meaning vs large KD meaning

A

small KD=receptor has high affinity for ligand

large KD=receptor has low affinity for ligand

93
Q

Ligand/receptor binding

Saturation binding relation

A

[LR]=([R]o[L]o)/(KD+[L]o)
or
Bound=Bmax(Free/(KD+free))

where Bmax is total number of receptors

94
Q

ligand/receptor binding

saturation plot

A

On free (x) vs bound (y) plot

KD is x/free value when bound=1/2*Bmax

So if Free»Kd, bound=Bmax
if free=Kd, bound=0.5Bmax (effective receptor)

95
Q

Assumptions in saturation binding relation (5)

A
  • equilibrium conditions
  • homogeneous, monovalent (1:1) populations of ligand and receptor
  • negligible ligand depletion (bound<10% of free)
  • negligible inactivation of ligand and receptor
  • negligible cell surface interactions
96
Q

Scatchard relation

A

[LR]/{L]o=([R]o/KD)-(1/Kd)[LR]
or
Bound/free=Bmax/Kd - 1/Kd*bound

97
Q

Scatchard plot

slope/yint/xint and implications

A

bound (x) vs bound/free (y)

slope= -1/Kd
yint=Bmax/Kd
xint=Bmax

steeper slope=smaller Kd=better binding

98
Q

Scatchard plot advantages/disadvantages

A

Advantage: easily visual evaluation for comparing different ligand/receptors or checking original assumptions

Disadvantage: bound on both axes magnifies experimental error–> should get Kd and Bmax from non linear reg

99
Q

Dose response plot

A

ligand concentration (x) vs fraction of maximum response or binding (y)

response can be anything downstream from receptor

EC50 (half maximal effective concentration) is x value where R/Rmax=1/2* Rmax=0.5

If EC50

100
Q

Saliva stimulation in diabetes

A

Showed that diabetic rats had fewer ACh receptors with normal KDs in parotid gland, could contribute to reduced saliva stimulation.

All other results shaky at best due to poor fits of plots.

101
Q

Ideal properties of second messangers (3)

A
  • rapid generation
  • small size and ability to easily diffuse
  • quick removal from system
102
Q

3 classes of second messangers

A

ions, water soluble molecules, membrane associated molecules

103
Q

cAMP source
cyclic adensosine monophosphate
second messanger

A

ATP

104
Q

cAMP effector enzyme
cyclic adensosine monophosphate
second messanger

A

adenylate cyclase at plasma membrane. Both N and C terminal catalytic domains in cytoplasm

105
Q

cAMP main function
cyclic adensosine monophosphate
second messanger

A

activates PKA (cAMP dependant protein kinase)

106
Q

cAMP location
cyclic adensosine monophosphate
second messanger

A

cytoplasm

107
Q

cGMP location

second messanger

A

cytoplasm

108
Q

cGMP source

second messanger

A

GTP

109
Q

cGMP effector enzyme

second messanger

A

guanylate cyclase (soluble, or catalytic domain of membrane associated)

110
Q

cGMP main function

second messanger

A

activates PKG

111
Q

IP3 location
1,4,5-inositol triphosphate
second messanger

A

cytoplasm

112
Q

IP3 source
1,4,5-inositol triphosphate
second messanger

A

PIP2 cleaved by phospholipase C to form cytosolic IP3 and membrane bound DAG

113
Q

IP3 effector enzyme

1,4,5-inositol triphosphate

A

PLC

phospholipase C family

114
Q

IP3 main function

1,4,5-inositol triphosphate

A

release Ca2+ from ER

can cause PKC activation

115
Q

DAG location

diacylglycerol

A

membrane

116
Q

DAG source

diacylglycerol

A
  • mainly from PC (PC cleaved by phospholipase D to form PA and choline, PA cleaved by PAP to form DAG and phosphate)
  • also from PIP2 (PIP2 cleaved by phospholipase C to form cytosolic IP3 and membrane bound DAG) and PE
117
Q

DAG effector enzyme

diacylglycerol

A

PLC (for PIP2), PLD/PAP (for PC and PE)

118
Q

DAG main function

diacylglycerol

A

activates PKC

119
Q

AA location

Arachidonic acid

A

membrane

120
Q

AA source

Arachidonic acid

A

mainly from PC
also from PE, PI (and derivatives PIP, PIP2)

phospholipase A2 cleaves and leaves membrane bound AA

121
Q

AA effector enzyme

Arachidonic acid

A

PLA2

phospholipase A2 family

122
Q

AA main function

Arachidonic acid

A

percursor for eicosanoids (for paracrine/autocrine signalling)

Source for membrane lipid reformation

123
Q

PIP3 location

phosphatidylinositol-3,4,5-triphosphate

A

membrane

124
Q

PIP3 source

phosphatidylinositol-3,4,5-triphosphate

A

PIP2

125
Q

PIP3 effector enzyme

phosphatidylinositol-3,4,5-triphosphate

A

PI-3K

phosphoinositide-3-kinase family

126
Q

PIP3 main function

phosphatidylinositol-3,4,5-triphosphate

A

activates PKB, PDK1 (phosphoinsoditide-dependant protein kinase 1)
–>activator of kinases recruited to membrane via PH domains

127
Q

Calcium concentrations for on/off

A

low <10^-7 is OFF

higher >10^-6 ON

128
Q

Calcium pumps (Ca signalling OFF)

A

Plasma membrane:
NCX: Na/Ca antiporter (low affinity, high rate)
PMCA: Ca ATPase (high affinity, low rate, 1ATP/Ca)

Sarco/ER:
SERCA: Ca ATPase (high affinity, low rate, 2ATP/Ca)

129
Q

Calcium channels (Ca signalling ON)

A

Plasma membrane:

  • ligand gated (cation selective) in nerve and smooth muscle
  • voltage gated (AP responsive) in nerve, muscle, endocrine

Intracellular:

  • IP3 receptors everywhere, need Ca and IP3
  • ryanodine receptors (RyR) in skeletal/cardiac muscle only need Ca
130
Q

CICR

A

calcium induced Ca2+ release

part of calcium ON mechanism

131
Q

Ca2+ sensors (name/general location)

A

Troponin C (TNC): skeletal/cardiac muscle, controls actin-myosin interaction

Calmodulin (CaM): in all cells, mediates lots

132
Q

Calmodulin structure/action

A

2 loops in 2 domains have negative amino acids to bind Ca2+ and cause conformational change (stretched out with long alpha helix in center)

Interacts with downstream serine/threonine specific protein kinases, phosphatases, PMCA pumps, adenylate cyclases

133
Q

Ca/CaM dependant protein kinase

CaM-Kinase II

A
  • Ca binds to CaM, with complexes with the kinase to form an activated complex
  • complex autophosphorylates using ATP to become fully active
  • complex dissociates into 3 parts
  • kinase still 50-80% active and is Ca independant
  • deactivated by phosphatase
134
Q

Toxin effect on cAMP (cholera and pertussis)

A

Cholera: stimulatory alpha subunit of g protein cannot unbind from adenylate cyclase so increase in cAMP (increased PKA activation, Cl channel opening, lots off loss of water and Na into intestine)

Pertussis: inhibitory g protein cannot dissociate (stays as alpha, beta gamma complex) so cannot bind adenylate cyclase (increased PKA activation, high insulin, low glucose causing seizures and high histamine, low pressure causing shock)

135
Q

cAMP termination

A

cAMP phosphodiesterase uses H20 to make 5’-AMP

136
Q

cGMP action

A

Membrane associated guanylate cyclase: hormone binds, cGMP formed.

Soluble guanylate cyclase: NO diffuses through membrane into cytoplasm causing formation of cGMP

PKG activated, enzymes phosphorylated

137
Q

cGMP termination

A

cGMP phosphodiesterase uses H2O to make 5’-GMP

138
Q

PIP/PIP2/PIP3 formation

A

PI to PIP via PI-4 Kinase

PIP to PIP2 via PI-5 kinase

PIP2 to PIP3 via PI-3 kinase

(reverse via phosphatases)

139
Q

Phospholipid derive second messanger compounds (4)

A

IP3, DAG, AA, PIP3

140
Q

IP3 and DAG action

A
  • PIP2 cleaved by phospholipase C to form cytosolic IP3 and membrane bound DAG
  • IP3 opens IP3 sensitive Ca channel
  • Ca and DAG activate PKC to cause phosphorylation of substrates
141
Q

Insulin pathway

A
  • insulin binds to alpha subunit of enzyme linked receptor
  • conformational change and autophosphorylation of beta subunit
  • coupling IRS protein’s PTB domain binds phosphorylated tyrosine
  • SH2 domain of PI-3K effector protein binds and becomes active
  • PIP2 phosphorylated to PIP3
  • PDK1 moves to plasma membrane, activated, phosphorylates PKB (both have PH domain)
  • PKB leaves membrane and causes vesicle with GLUT4 to fuse to plasma membrane
  • GLUT4 moves glucose into cell
142
Q

Insulin receptor structure

A
  • receptor tyrosine kinase
  • constitutive heterotetramer (2 extracellular alpha, 2 transmembrane beta) held together with disulfide bonds
  • alpha have cysteine rich domains
  • beta have tyrosine kinase domains
143
Q

Type 2 diabetes therapy goal

A

-decrease insulin resistance (caused by elevated insulin in blood) and delay insulin therapy by targeting insulin receptor or post receptor pathway

144
Q

Salivary glands secretion composition and %volume

A

Submandibular: 70%, mixed mostly serous
Parotid: 25%, serous
Sublingual: 5%, mixed mostly mucous

145
Q

Saliva secretion pathway (Fluid)

A

PSN:

  • Ach binds to muscarinic ACh receptor (g protein coupled receptor), causing conformational change
  • G protein activated with GTP dissociates
  • active alpha subunit activates PLC in membrane
  • PLC cleaves PIP2 to form DAG and IP3
  • IP3 in cytoplasm binds to IP3 ligand gated ion channel receptor causing release of Ca2+
  • other pumps and channels activated forming osmotic gradient causing secretion of water and ions
  • termination via PK phosphorylation
146
Q

Saliva secretion pathway (proteins)

A

SNS: protein secretion pathway, Norepi, causes increased cAMP

  • Norepinephrine binds to beta-adrenergic g protein coupled receptor causing conformational change
  • g protein activated with GTP then dissociates
  • active alpha subunit activates adenylate cyclase in plasma membrane
  • cAMP formed from ATP
  • cAMP activates PKA
  • exocytosis of preformed protein-containing vesicles and synthesis/packaging of new vesicles
147
Q

Xerostomia therapies

A
  • want long lasting, selective treatment to increase saliva secretion
  • target muscarinic ACh receptor using agonists (cholinomimetics)
148
Q

Odontoblast layer of human teeth

A
  • bacteria/by-products diffuse through dentinal tubules
  • bind to odontoblast receptor
  • production/release of cytokines, antimicrobial peptides, chemokines
  • amplification via autocrine and paracrine (macrophages/immunecells/dendritic cells) signalling
149
Q

insulin receptor

A
  • enzyme linked recepter

- constitutive heterotetramer

Biochem 3 (5 decks)

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