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BS129: Physiology, Neurobiology and Metabolism > Signal Transduction (Lecture 14-19) > Flashcards

Signal Transduction (Lecture 14-19) Flashcards

1
Q

Examples of cell behaviour controlled by signals

A
  • Growth
  • Differentiation and dvelopment
  • Metabolism
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2
Q

Name some signals for bacteria

A
  • pH
  • Osmotic strength
  • Food
  • Oxygen
  • Light
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3
Q

What do bacteria do when they recieve a signal?

A

Signal → receptor → response

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4
Q

Define signaling

A

Information from beyond the plasma membrane

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5
Q

Define a receptor

A

Information detector

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6
Q

Define amplification

A

Small signals are usually amplified within the cell to give a large response

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7
Q

Define response

A

Chemical changes and/or changes in gene expression

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8
Q

Describe direct contact

A
  • A protein (ligand) on the signalling cell binds a protein (receptor) on the target cell
  • Target cell responds
  • Common in tissue development
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9
Q

Describe gap junction

A

Exchange small signalling molecules and ions, coordinating metabolic reactions between cells

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10
Q

Examples of gap junction

A
  • Gap junctions are made and broken during embryo development
  • Electrical synapse use gap junctions between neurons for rapid electrical transmission
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11
Q

What enables the passage of electrical currents?

A

Clusters of gap junctions which connect the interior of 2 adjacent neurons

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12
Q

Describe autocrine signalling

A
  • Ligand induces a response only in the signalling cell
  • Autocrine ligands are typically rapidly degraded in the EC medium
    • Used to enforce developmental decisions
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13
Q

Describe eicosanoids in terms of autocrine signalling

A
  • Autocrine ligands derived from fatty acids
  • Exert complex control
    • Aggregation of platelets in the immune system
    • Integration of pain and inflammatory responses
      • Aspirin (antagonist)
    • Contraction of smooth muscle
  • Common feature of cancers
    • Auto-production of growth hormones stimualtes cell proliferation
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14
Q

Describe paracrine signalling

A
  • Ligand induces a response in target cells close to signaling cell
  • Diffusion of the ligand is limited
  • Destroyed by EC enzymes
  • Internalized by adjacent cells
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15
Q

Example of paracrine signalling

A

Neuromuscular junctions

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16
Q

Describe the process of neuro-muscular junctions and paracrine signalling

A
  • Nerve impulse stimulates the movement of synaptic vesicles which fuse w the cell membrane
  • This releases acetylcholine
  • Acetylcholine stimulates channel opening, allowing for ion exchange
  • The muscle twitches and acetylcholinesterase degrades the acetylcholine
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17
Q

Describe endocrine signaling

A
  • The ligand is produced by endocrine cells and is carried in the blood
  • This induces a response in distant target cells
  • Ligands are often called hormones
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18
Q

Explain cell-type specific expression

A
  • Certain receptors are only present on certain cells
    • TRH triggers pituitary responses but not liver responses
  • Molecules downstream of the receptor are only present in some cells
    • Epinephrine (adrenaline) alters glycogen metabolism in hepatocytes but not in erythrocytes
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19
Q

Explain high affinity interactions

A
  • Precise molecular complementarity between ligand and receptor
  • Mediated by non-covalent forces
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20
Q

How are signals amplified by enzyme cascades?

A
  • Receptor/enzyme associated w receptor is activated
  • Catalyzes activation of second enzyme → activate multiple molecules of a third molecule
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21
Q

Examples of desensitization in signaling

A
  • Walking from bright light to dark room
    • Visual transduction system has become desensitized
  • Noxious smells
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22
Q

Describe how EGFR signalling occurs

A
  • Highly specific, high affinity interaction
  • Differential EGFR expression
    • Epithelial cells +
    • Hematopoetic cells -
  • Amplification by the MAPK enzyme cascade
  • Desensitization by dephosphorylation of EGFR
  • Cross-talk n integration w other signalling pathways
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23
Q

Following translation, the IR subunuits:

A
  • Enter the ER membrane
  • Associate into dimers
  • Exported to the cell surface via the Golgi complex
  • During intracellular transport, the proteins are processed by z proteolytic cleavage, each into an alpha n beta subunit
  • At the plasma membrane, they are displayed as trans-membrane proteins
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24
Q

Describe how insulin activates the IR at the cell surface

A
  • Insulin binds to IR and stimulates change (allosteric change)
  • This brings cytosolic domains close to each other
  • Each of these domains are a kinase so activation leads to auto transphosphorylation
  • This results in activation of IR
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25
Q

TERM: Ligand

A

EC substance (e.g. epinephrine, serotonin) that binds to a cell surface receptor n initiates signal transduction that results in a change in IC activity

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26
Q

TERM: Receptor

A

Protein that binds n responds to the first messenger

Receptor may be either displayed at the cell-surface (e.g. IR, EGFR, GPCRs) or may be intracellular

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27
Q

Why is IRS-1 bifunctional?

A
  • Recruits n activates PI-3K
  • Binds to phosphorylated tyrosine residues on the receptor through PTB domain
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28
Q

TERM: second messenger

A

Small metabolically unique molecule (not protein) whose concentrations can change rapidly

Relay signals from receptors to target molecules in the cytoplasm or nucleus

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29
Q

Describe glucose regulation

A
  • Activation of the receptor
  • Recruitment of a kinase that can phosphorylate a membrane lipid
  • Amplifies sequence (second messenger)
  • Lipid allows recruitment n activation of PKB
    • PKB responsible for setting in motion events that reduce glucose lvl in the blood
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30
Q

Explain why insulin is a growth factor

A
  • Phosphorylation of IRS-1 amplifies the signal
  • Adaptors recruit n activate Ras
  • Signal transduction via an amplifying MAPK cascade
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31
Q

Explain why insulin is a blood glucose regulator

A
  • Phosphorylation of IRS-1 amplifies the signal
  • Signal propagation n amplification via conversion of membrane lipids
  • Amplification via lipid dependent kinase n activation of PKB
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32
Q

Describe the cellular responses to insulin within minutes

A
  • Increased uptake of glucose into muscle cells n adipocytes
  • Altered glucose metabolism by modulation of enzyme activities
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33
Q

Describe the cellular responses to insulin within hours

A
  • Increased expression of:
    • Liver enzymes → synthesize glycogen
    • Adipocyte enzymes → synthesize triacyclglycerols
    • Genes involved in some cell lines
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34
Q

How is the insulin signaling system normally turned off?

A
  • PTEN removes phosphate at the 3 position of PIP3, converting it into PIP2
  • PDKI n PKB can no longer be recruited to plasma membrane, shutting off signaling thru PKB
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35
Q

How do we deal w blood sugar?

A
  • As glucose is removed from the blood, activation of PTEN occurs which shuts the system down
  • Activated PKB stimulates movement of storage vesicles to cell surface
    • In these vesicles hv GLUT4 transporter in their membrane
    • GLUT4 is now expressed at the cell surface
    • Substrate for GLUT4 is glucose
      • Binding causes allosteric change allowing glucose to enter the cell
  • Reduction of blood glucose lvl in muscle n fat tissue
  • PKB regulates conversion of any excess glucose that cannot be used via glycolysis into glycogen n triacylglycerols
  • If you can’t make or respond to insulin then you hv high blood glucose levels
36
Q

Describe the basic structure of GCPR

A
  • EC domains
    • E1 n loops E2-4
  • Trans-membrane domains
    • TM1-7
  • Cytosolic domains
    • Loops C1-C3
    • C4 tail
  • C4 has a lipid anchor
37
Q

What is the heterotrimeric G-protein made of?

A

Trimer of alpha, beta n gamma subunits

38
Q

What happens after Gα activation?

A
  • G-protein dissociates from receptor
  • Yields a Gα-GTP monomer n a tightly interacting Gβγ-dimer
  • They now modulate the activity of other IC proteins
39
Q

How do heterotrimeric G proteins cycle b/w on n off states?

A
  • Gα has slow GTP hydrolysis activity
    • Regenerates inactive form of α-subunit (Gα-GDP)
      • Allows reassociation w Gβγ-dimer to form “resting G protein”
  • Resting G protein can bind to GPCR n await activation
40
Q

What does Gs do?

A
  • Stimulates adenylate cyclase
  • Signals glucagon n epinephrine
41
Q

What does Gi do?

A
  • Inhibits adenylate cyclase
  • Signals for adenosine, prostaglandin
42
Q

What is the effect of cortisol on blood sugar levels and the immune system?

A
  • Increases blood sugar thru glucogenesis
  • Suppresses the immune system
43
Q

What are adrenergic receptors?

A

G protein coupled receptors that bind to the hormones epinephrine n norepinephrine

44
Q

What are the effects of binding to alpha-adrenergic receptors?

A
  • Inhibits insulin secretion by the pancreas
  • Stimulates glycogenolysis in the liver and muscle
  • Stimulates glycolysis in muscle.
45
Q

What are the effects of binding to beta-adrenergic receptors?

A
  • Triggers glucagon secretion in the pancreas
  • Increased lipolysis by adipose tissue
  • Leads to increased blood glucose n fatty acids for energy production
46
Q

Describe what happens when epinephrine binds to β-adrenergic GPCR receptor

A
  • Gαs is activated
  • Stimulates adenylate cyclase
  • RESULT: increase in cAMP levels in the cell
47
Q

Why is cAMP a second messenger?

A
  • Signaling molecule in all cells
  • Activates a variety of proteins
48
Q

What are PKA’s targets?

A
  • Transcription factors
  • Ion channels
  • Other enzymes
49
Q

Role of cAMP in cells

A

Activates a variety of target proteins

50
Q

When epinephrine binds to a β-adrenergic GPCR receptor coupled w a Gs heterotrimeric G protein?

A
  • Activates Gas → stimulates adenylate cyclase
  • Gβs subunits inhibits adenylate cyclase
51
Q

When epinephrine binds to a α-adrenergic GPCR receptor coupled w a Gi heterotrimeric G protein?

A
  • Gαi activated → inhibits adenylate cyclase
  • Gβγi subunits activate a MAPK cascade
52
Q

How does CTx traffic to the ER of target cells?

A
  • CTx binds to cell surface of ganglioside lipid GM1 on target intestinal epithelial cells
  • CTx undergoes retrograde trafficking via endosomes n Golgi complex to ER
  • Disulfide bond b/w CTXA1 n CTxA2 is broken by PDI → helps CTx become unfolded n makes it easier to move across the ER membrane
    • PDI: protein disulfide isomerase (ER resident protein)
  • BiP keeps CTxA1 soluble until it dislocates across ER membrane in an unfolded form
    • BiP (binding protein)
  • CTxA1 refolds in cytosol
53
Q

Function of CTxA

A
  • ADP-ribosylase
  • Transfers a ribose group onto a specific arginine on Gas
    • Locks Gas in active state permanently → cannot degrade GTP
54
Q

What is the consequence of CTx locking Gas in its active state?

A

Adenylate cyclase turned on permanently → cellular cAMP levels rise to over 100 fold abv normal

55
Q

What is the consequence of increased cAMP levels caused by CTx?

A
  • Activates CFTR membrane channels → increased efflux of Na+ and water into the intestine
  • Causes massive secretory diarrhea → death from dehydration
56
Q

How does light reception work in the vertebrate eye?

A
  • Light passes neural layer thru cell bodies of light receptor cells (rods n cones)
  • Acts as a signal in the photoreceptive membrane disc in the “outer segment” of the retina
57
Q

What are the primary cilium extensions from the surface of vertebrate cells?

A

Extensions from the surface of most vertebrate cells that act as signalling organelles.

58
Q

How do rod cells differ from cone cells in their response to light intensity?

A
  • Rod cells → non-colour vision at low light intensity
  • Cone cells → colour vision at high light intensity
59
Q

What is the structure of the outer segment of a rod cell?

A
  • ~1000 discs that are not connected to plasma membrane
  • Each disc in the outer segment of a rod cell is a closed sac of membrane with embedded photosensitive rhodopsin molecules.
60
Q

What are rhodopsin molecules responsible for?

A

Detecting light n initiating signal transduction cascade in rod cells

61
Q

What is rhodopsin made of?

A
  • GPCR
  • Opsin (GPCR protein component)
  • Linked to 11 cis retinal (prosthetic group that is the chromophore / light absorbing group)
62
Q

How is light energy converted into atomic motion?

A
  • Alternating single n double bonds form polyene w a long unsaturated network of electrons that can absorb light energy
  • Light absorption causes cis-trans isomerization around C12 n C13 bond
  • N of key lysine moves 5A
63
Q

Describe the relationship light absorption n GPCR

A
  • Light absorption by retinal → conformation of GPCR
    • Inactive rhodopsin becomes activated metarhodopsin II
  • Metarhodopsin stimulates nucleotide exchange on the α-subunit of a specific heterotrimeric G protein called transducin (Gt)
64
Q

How does transducin Gαt activates cGMP phosphodiesterase?

A
  • Light activates rhodopsin, which activates the Gt transducin (Gαt, Gβt, Gγt)
  • GTP stimulates cGMP phosphodieseterase (GcMP PDE) which removes cGMP from cGMP-gated ion channels
65
Q

What happens when the cGMP-gated ion channels close?

A
  • Membrane becomes hyperpolarized
  • Thus, light stimulus has been converted to a change in electrical potential across membrane
66
Q

How does light affect the concentration of calcium ions in rod cells?

A
  • Light closes cGMP gated ion channels → reduces influx of Ca++
  • Ca++ is extruded by Na+/Ca++ antiporters → Ca++ concentrations in cell fall
  • Low Ca++ activates guanylate cyclase
    • cGMP levels rise
    • Channels re-open → read to be closed again by light
67
Q

How does the phosphorylation of rhodopsin affect the activation of transducin?

A
  • Reduces the activation of transducin
  • There are 7 phosphorylation sites
    • Higher light intensity, more sites are phosphorylated
  • Higher phosphorylation → lower ability to activate transducin
68
Q

Describe how very high light intensity reduces the activation of transducin

A
  • Light activates rhodopsin
  • Light-activated rhodopsin can be phosphorylated by rhodopsin kinase
  • Arrestin binds to fully phosphorylated rhodopsin → stops activation of transducin
69
Q

What are the 3 mechanisms that make rods insensitive to high light?

A
  • Prolonged cGMP-gated channel closure
  • Phosphorylation of opsin reduces transducin activation
  • Arrestin binding to phosphorylated opsin stops transducin activation
70
Q

Describe the structure of the photoreceptor

A
  • Opsin (modified GPCR)
  • 11-cis-retinal (chromophore)
  • Different transducin
71
Q

How do amino acid differences in the modified GPCR affect color tuning?

A
  • Alter the electronic environment that surrounds the 11-cis-retinal chromophore
  • Chromophore responds (cis-trans isomerization) to different frequencies of light
72
Q

What eye adaptations do cephalopods have to help them judge color?

A
  • Cephalopods have wide pupils that accentuate chromatic aberration → detect and focus on narrow bands of wavelengths
  • Change the depth of their eyeball → alter the distance between the lens and the retina
  • Move the pupil around to change its off-axis location → adjust the amount of chromatic blur and further refine their perception of color.
73
Q

How do cephalopods judge color?

A

Bringing specific wavelengths to a focus on their retina

Achieve this by using eye adaptations to adjust the amt of chromatic blur n refine perception of colour

74
Q

What is chromatic aberration, and how do cephalopods use it to detect color?

A
  • Different wavelengths of light are refracted differently by a lens, causing them to focus at slightly different points
  • Cephalopods hv wide pupils that accentuate chromatic abberrtion → allows to detect n focus on narrow bands of wavelengths → used to perceive colour
75
Q

How does nitric oxide signal?

A
  • Nitric oxide diffuses across plasma membrane
    • Binds n activates to its receptor
  • Activated receptor (GC) converts GTP into cGMP
  • cGMP is a 2nd messenger that alters the activity of target proteins
76
Q

How do blood vessels normally dilate?

A
  • Response to high BP
  • Increases vessel volume → lowers BP
77
Q

Describe how NO* production in vivo is stimulated by high BP

A
  • Autonomous nerves in vessel wall respond to high BP n release Ach
  • Acetylcholine binds to AchR (receptors) on plasma membrane of endothelial cells
    • Stimulation by acetylcholine increases endothelial cell cytosolic [Ca++]
78
Q

How does Ca++ act as a second messenger?

A
  • High Ca++ activates nitric oxide synthase
  • NOS catalyzes conversion of arginine to citrulline n nitric oxide
79
Q

How does NO* act as a paracrine signal to smooth muscle?

A
  • NO* activates soluble guanylate cyclase
    • Binds to haem group → causes conformational chan
  • GC converts GTP to cGMP
    • cGMP: second messenger
80
Q

What is the role of PKG in smooth muscle relaxation and blood pressure regulation?

A
  • PKG is a cGMP-dependent protein kinase
    • Phosphorylates myosin light chain
  • Muscle cells w phosphorylated myosin light chain relax
  • Smooth muscle relaxation → dilation of blood vessel
  • Dilation increases volume of vessel n lowers BP
81
Q

Describe sidenafil’s mechanism of action

A
  • Sidenafil citrate is a cGMP mimic
    • Potent inhibitor of cGMP phosphodieseterases
    • Most active against phosphodieseterase 5
82
Q

What are the different domains of the ER?

A
  • N-terminal transactivation domain
  • DNA binding domain
  • Hormone binding domain
    • Can bind to estrogen
83
Q

How is the ER maintained in a soluble state?

A

The ER is stored in the cytosol in complex with Hsp90 (dimeric chaperone protein), which binds near the ligand-binding site and maintains the ER in a soluble state.

84
Q

Why can’t the Hsp90:ER complex enter the nucleus?

A
  • The Hsp90:ER complex is too large to enter the nucleus
    • ER needs to dissociate from Hsp90 before it can translocate into the nucleus to exert its function as a transcription factor.
85
Q

Describe how oestrogen-bound ER is a transcription factor

A
  • Estrogen diffuses across PM n binds to ER
  • ER is released from Hsp90
  • ER-estrogen complex enters nucleus n binds estrogen response elements (EREs) as a dimer
  • Estrogen-responsive genes are transcribed
86
Q

What is the function of the ER in response to estrogen?

A
  • ER is the receptor for estrogen and, upon activation by estrogen, binds to DNA and directs transcription of estrogen-response genes.
  • This means that the ER is both the receptor and effector in this signaling pathway, and there are no amplification steps via protein cascades or second messengers.
87
Q

What is sildenafil most active against?

A

Phosphodiesterase type 5 (PDE-5)

BS129: Physiology, Neurobiology and Metabolism (2 decks)

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