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BGM2002 CS > L2 - Introduction to cell signalling II > Flashcards

L2 - Introduction to cell signalling II Flashcards

1
Q

What are the 3 general strategies used to transfer information across the PM?

A

Intracellular receptors
• Membrane-permeable small hydrophobic signals diffuse passively

Ion-coupled channels
• Signals bind to & regulate opening of membrane channels

Transmembrane receptors
• Signals bind to TM receptors - activation of intracellular enzymes

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2
Q

Intracellular receptors

A

Bound by small hydrophobic molecules that can pass through the hydrophobic membrane

Bind to nuclear receptors

Cellular response = relatively slow

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3
Q

How do steroid hormones work?

A
  1. Formation of a complex ligand-receptor
  2. Upon binding of the ligand, receptor becomes active
  3. Hormone-receptor complex translocates into the nucleus where it acts as a transcription factor turning on testosterone-responsive genes

Intracellular receptors

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4
Q

What can you call ion-coupled channels?

A

Ligand-gated ion channels
Ion-coupled channels
Ion-channel-coupled receptors

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5
Q

What are ligand-gated ion channels?

A

Transmembrane pores formed of multiple protein subunits

Key role in synaptic signalling: covert chemical signal (neurotransmitter) into electric signal (ion flow)

Cellular response = very rapid (milliseconds)

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6
Q

How do ligand-gated ion channels work?

A
  1. Ligand binds to extracellular part of channel
  2. Induces a conformational change of the receptor – opens the ion channels
  3. Results in a flow of small molecules such as ions across the cell membrane
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7
Q

Cell surface receptors

A

Most diverse & most commonly used
Most signal molecules are large and/or hydrophilic & cannot cross the PM so must bind to receptors

Each cell expresses a repertoire of TM receptors

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8
Q

What are transmembrane receptors?

A

Sensors that detect extracellular stimuli – act like a molecular switch

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9
Q

Cell surface receptor structure

A

EC ligand-binding site: highly specific & sensitive

1 or more hydrophobic transmembrane domains

IC portion of receptor coupled to downstream signalling

Receptor transduces EC signal into IC signalling cascade

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10
Q

2 common strategies used to transfer signals in cell surface receptors

A

Receptor conformational changes

Receptor clustering

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11
Q

3 main classes of transmembrane receptors

A

GPCR

Enzyme-linked receptor

Cytokine receptor

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12
Q

What are GPCRs?

A

7 transmembrane protein

Coupled with large protein G

Largest family of cell surface receptors in eukaryotes

Many functions: smell, taste, sight, endocrine function, neuronal communication

Many drugs act through GPCRs

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13
Q

What are enzyme-linked receptors?

A

The receptor has catalytic activity

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14
Q

What are cytokine receptors?

A

Receptor has no catalytic activity

Coupled to an intracellular enzyme

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15
Q

Process of GPCRs

A

Binding of ligand to EC domain induces a conformational change of receptor allowing its cytosolic domain to bind to & activate the G protein

G protein acts as an on/off switch: if GTP is bound to the G protein it is active

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16
Q

What are G proteins composed of?

A

3 subunits
• Alpha - binds GDP & GTP
• Beta & Gamma

2 lipid anchors

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17
Q

Activation of G proteins

A
  1. G protein is inactive & binds GDP
  2. GPCR binds its ligand & induces a change of conformation
  3. Alpha subunit binds GTP instead of GDP & becomes active
  4. Alpha subunit dissociates from beta & gamma & migrates to target protein
  5. Target protein activated
  6. 2nd messenger produced
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18
Q

Deactivation of G proteins

A
  1. Alpha subunit hydrolyses GTP by GTPase activity
  2. Alpha dissociates from target protein
  3. Alpha re-associates with beta & gamma
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19
Q

Example of GPCR signalling

Epinephrine receptor

A

Response to stress

Adenylyl cyclase produces cAMP which is the second messenger

Acts on multiple effectors

Allows person to run faster

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20
Q

Abnormal G-protein signalling can be caused by…

A

Cholera bacterial toxins

Gene mutations

Single nucleotide polymorphisms

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21
Q

How do cholera bacterial toxins cause abnormal G-protein signalling?

A

Binds to alpha subunit  inactivates GTPase activity

Leads to defective signal termination with persistent elevated levels of cAMP & effector activity (loss of salt from epithelial cells of the intestine)

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22
Q

What types of gene mutations cause abnormal G-protein signalling?

A

Loss of function
• Signalling in response to the corresponding agonist
• Receptor becomes resistant to signal

Gain of function
• Leads to constitutive, agonist-independent activation of signalling

Mis-folding of GPCR
• Receptor retains its function but located in parts of cell where function in inappropriate

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23
Q

How do single nucleotide polymorphisms cause abnormal G-protein signalling?

A

Impact of SNPs on individual variations in response to drug as GPCRs mediate the therapeutic effects of more than 30% of FDA-approved drugs

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24
Q

What are receptor tyrosine kinases (RTKs)?

A

Single transmembrane span receptors
An enzyme coupled receptor

Extracellular side – ligand binding site
Cytoplasmic side – Tyr kinase domain & tyrosine’s

2 forms:
– Monomeric inactive
– Dimeric active

A RTK can trigger multiple signal transduction pathways at once

Autophosphorylation increases the catalytic efficiency of the receptor & provides binding sites for the assembly of downstream signalling complexes

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25
Q

RTK activation steps

A
  1. A bivalent ligand binds simultaneously to 2 RTKs inducing a dimerisation of monomeric RTKs
  2. Dimerisation activates Tyr kinase activity
  3. Autophosphorylation of Tyr domains
  4. RTKs interact with & activate proteins
  5. Cellular response
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26
Q

Structure of RTKs

A

EC domain
• Highly variable binding
• Recognition of various signals

TM domain
• Small
• Hydrophobic

IC domain
• Common: Tyr kinase domain
• Some kinase domains are interrupted by inserts

27
Q

What is the EGF receptor?

A

Receptor for Epidermal Growth Factor (EGF)

Member of the ErbB family involved in angiogenesis, apoptosis, cell proliferation & metastasis

28
Q

Activation of the EGF-R

A

Activation of the EGF-R by EGF

Phosphorylation of tyrosine of cytoplasmic proteins

Signals to the cell to proliferate & grow

29
Q

Deregulation of EGF-R in cancer

A

Don’t need a ligand to activate the receptor in cancer cells

1 or more members of the family of EGRF genes are overexpressed or deregulated in most epithelial tumours by: 
– Activating mutation 
– Increase gene copy number 
– Overexpression 
– Truncation of receptor EC domain
30
Q

Cytokine receptors: JAK-STAT signalling

A

Large family of receptors

Activated by cytokines (interferon & interleukins) or growth factors (prolactine & EPO)

Control synthesis & release of inflammatory mediators

Receptor has no catalytic activity but associated with kinase

31
Q

What are the 3 main components of the JAK-STAT signalling pathway?

A

Receptor

Janus Kinases (JAK)

STATs

32
Q

Receptors in the JAK-STAT signalling pathway

A

Binds to cytokine or growth factor

Receptor forms a dimer

33
Q

Janus Kinases (JAK) in the JAK-STAT signalling pathway

A

‘Just Another Kinase’

Dimeric receptors associate with Janus Tyrosine Kinases (JAKs) & activate JAKs which:
• Cross phosphorylate each other
• Phosphorylate & activate R
• PO4- creates a docking site for SH2 domains of transcription regulators STATs
• JAKs phosphorylate & activate STATs

34
Q

STATs in the JAK-STAT signalling pathway

A

Transcription regulators STAT: Signal Transducers & Activators of Transcription

Dissociate from the receptor & dimerise

Dimer migrates to the nucleus where it binds to promoter region & activates transcription of target genes

35
Q

JAK-STAT signalling: example of leptin

What is leptin?

A

Satiety hormone – feeling of being full

Is produced by adipose (fat) tissue

Reduces food intake, controls metabolism & body weight

36
Q

JAK-STAT signalling: example of leptin

The leptin receptor

A

Cytokine receptor in brain satiety centre

Binding of leptin to its receptor activates JAK proteins that phosphorylate tyrosine residues on the leptin receptor, allowing for the recruitment & phosphorylation of STATs

STAT proteins dimerise, translocate to the nucleus & act as transcription factors stimulating expression of genes that inhibit appetite

37
Q

Feedback & adaptation at receptor level

A

Receptor sequestration

Receptor down regulation

Receptor inactivation

Inactivation of signalling protein

Production of inhibitory protein

38
Q

Intracellular receptors

Response time & effects

A

HOURS

Alter gene transcription & protein expression

39
Q

Ligand gated ion channels

Response time & effects

A

MILLISECONDS

Alter membrane potential

40
Q

GPCRs

Response time & effects

A

SECONDS

Can mediate 2nd messengers or can directly activate the ion channels

41
Q

Enzyme-linked receptors / cytokine receptors

Response time & effects

A

HOURS

Alter gene transcription & protein expression

42
Q

What is transduction?

A

Signal relay, amplification & integration

Requires transducer molecules

43
Q

Transducer molecules

A

Signalling proteins
• Kinases, Phosphatases, GTPases, Adaptors

Second messengers
• cAMP & cGMP, Lipids, Calcium, NO

Often act as molecular switches

44
Q

Signal transduction cascade

A 
Multistep process during which transducers: 
• Relay 
• Transduce 
• Amplify 
• Integrate 
• Regulate
45
Q

Signal transduction cascade

TRANSDUCTION

A

At each step, signal transduced into a different form, commonly protein conformational change

46
Q

Signal transduction cascade

AMPLIFICATION

A

Signal amplified by activating multiple copies of next component in pathway

47
Q

Signal transduction cascade

INTEGRATION

A

Coordinate, distribute, regulate signal

Allow fine tuning of the response & contribute to response specificity

48
Q

Signal transduction cascade

REGULATION

A

Many signalling pathways are regulated by post-translational modifications

Phosphorylation, ubiquitination & acetylation

49
Q

Phosphorylation cascade

A

Reversible molecular switches

  1. Relay molecule activates kinase 1
  2. Active kinase adds phosphate to next kinase / effector in line, activating or inhibiting it
  3. Phosphatase removes PO4-, deactivating the kinase which can be reused – no need for protein synthesis
  4. Signal is amplified at each stage
50
Q

Adaptor proteins

A

Have no intrinsic enzymatic activity

Usually contain several protein-binding domains or modules

These modules or motifs mediate intermolecular interactions between receptors & specific target proteins

51
Q

How do adaptor proteins mediate intermolecular interactions between receptors & specific target proteins?

A

Act as docking proteins that link receptors with other effector proteins

Scaffold the organisation of large protein complexes between protein-binding partners

Dictate:
• Specificity of interactions between binding partners
• Subcellular localisation of binding partners

Integrate signals from different pathways (cross-talks) & coordinate responses

Adaptor proteins regulate cell signalling in a spatial & temporal manner

52
Q

Adaptor protein Grb2 recruitment to EGFR-phospho-Tyr activates Ras & MAPK signalling cascade cascade in response to mitogens

A
  1. EGF binds to the receptor activating TK
  2. Autophosphorylation of the receptor
  3. SH2 binds phosphorylated tyrosine
  4. Sos binds SH2 by SH3 & converts GDP to GTP on Ras to activate it
  5. Ras phosphorylates RAF
  6. RAF phosphorylates MEK
  7. MEK phosphorylates MAP kinase which causes the response
53
Q

What are second messengers?

A

Chemical relays from plasma membrane to cytoplasm - short lived

Small, non-protein, water-soluble molecules or ions

Greatly amplify the strength of a signal

54
Q

2nd messenger information is encoded by local concentrations

A

Elevated concentration  triggers rapid alteration of activity of cellular enzymes

Removed or degraded  terminates cellular response

55
Q

What are the 3 basic types of 2nd messenger molecules?

A

Hydrophobic molecules: membrane-associated

Hydrophilic molecules: water-soluble molecules in cytosol

Gases: can diffuse through cytosol & across membrane

56
Q

cAMP signalling pathway

A
  1. Activation of GPCRs by hormone
  2. G-protein (G-alpha-stimulatory) activates adenylyl cyclase
  3. AC catalyses cAMP synthesis from ATP
  4. cAMP binds PKA regulatory subunits (Protein Kinase A – cAMP-dependent PK)
  5. Dissociation from the catalytic subunits

Catalytic subunits of PKA:
• FAST response: PKA-C phosphorylates enzyme in the cytoplasm (eg. glycogen phosphorylase)
• SLOW response: PKA-C enters the nucleus & phosphorylates transcription factors such as CREBP (cAMP response element binding protein). CREBP binds to promoters (CRE) & turns on gene expression

57
Q

Inactivation of cAMP signalling pathway

A
  1. EC ligand/receptor binding reversible
  2. Deactivation of G protein by hydrolysis of GTP to GDP
  3. Phosphodiesterase breaks down cAMP: decrease in [cAMP] in cell
  4. Phosphatase removes phosphate on target effector
58
Q

Other 2nd messengers

A

NO

cGMP

59
Q

NO as a 2nd messenger

A

Gas, free radicals, diffuses across plasma membrane & affects nearby cells

Synthesised from arginine & oxygen by NO synthase

NO activates guanylyl cyclase which synthesises cGMP – toxic at high concentration

60
Q

cGMP as a 2nd messenger

A

Synthesised from GTP using guanylyl cyclase in response to NO

Triggers cell response by activating cGMP-stimulated kinase or Protein Kinase G (PKG)

cGMP induces blood vessel relaxation (smooth muscles)

Phosphodiesterase breaks down cGMP

61
Q

2nd messengers involved in the Inositol Phospholipid Pathway

A 
Combination of several 2nd messengers: 
• DAG
• PIP
• IP3
• Ca2+
62
Q

Inositol Phospholipid Pathway

A
  1. Activation of GPCRs
  2. G-protein (G-alpha-q) activates phospholipase C
  3. PLC hydrolyses PIP2 to DAG & IP3
  4. DAG (hydrophobic) recruits to membrane & activates PKC
  5. IP3 (soluble) diffuses through cytosol, binds receptors on ER triggering Ca2+ release into the cytosol
  6. Ca2+ binds to effector proteins:
    – PKC: increases its activation
    – Calmodulin – cytosolic Ca2+ binding protein
63
Q

Cell response to the Inositol Phospholipid Pathway

A

Cell division

FAST: PKC phosphorylates effector protein

SLOW: calmodulin activates CAM-kinase (calmodulin dependent protein kinase) – CAM kinase phosphorylates transcription factors on the chromosome

BGM2002 CS (14 decks)

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