Cell Signalling

Question 1

What are signals?

Answer 1

Signals = usually small molecules, termed ligands which bind to a larger receptor which can be membrane-bound or cytosolic (soluble)
- signals can be short or long

Question 2

What are the 4 main types of cell signalling?

Answer 2

1. Autocrine - self stimulation - cell secretes a ligand that activates itself
2. Paracrine - in which a cell produces a signal to induce changes in local cells, altering the behaviour of those cells.
3. Endocrine - distant cells - usually involves glands - signals are produced by specialised cells and released into the bloodstream, which carries them to target cells in distant parts of the body. (hormones)
4. Juxtacrine - direct contact often via membrane bound ligands - cell–cell or cell–extracellular matrix signalling in multicellular organisms that requires close contact

Question 3

How can surrounded cells detect if a cell dies?

Answer 3

When a cell dies, it stops metabolising and producing ATP → resting potential no longer maintained by ion channels/pumps → creates an action potential → nearby cells detect signals and able to prepare themselves

• cells also lose control of oxidative stores → leads to oxidative membrane lipids, etc
• cell-cell communication important for uni and multicellular organisms

Question 4

What are the different signalling receptors?

Answer 4

5 main classes of cell signalling receptor:

1. Adhesion receptors (e.g integrins promote survival of cells bound to ECM)
2. Ligand-gated ion channels
3. Nuclear receptors
4. G-protein Coupled Receptors
5. Enzyme coupled receptors

Question 5

What are ligand gated receptors?

Answer 5

are a group of TRANSMEMBRANE ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

• *e.g ACh-gated Na+ channel**
  1. Ach binds to Ach receptor
  2. undergoes conformational change in shape
  3. stimulates signal which opens gate so Na+ passes
• *e.g Nicotinic acetylcholine receptor - ligand gated Na+ channel**
• found in musculoskeletal junctions, CNS synapses

→ Nicotine is an agonist (opens channels) (has similar structure to Ach)

→ Curare is an antagonist (blocks the channel, paralysis)

Question 6

What are nuclear receptors?

Answer 6

INTRACELLULAR

• Hydrophobic ligand modulated transcription factors
• are a superfamily of dimeric zinc finger transcription factors that bind lipid soluble hormones and interact with DNA binding regions

e.g oestrogen

1. Small lipid hormones diffuse through the plasma membrane and nuclear membrane to interact with transcription factors (control transcription activators)
2. When nuclear receptor bound to ligand, undergoes allosteric conformational change and allows for dimerisation which allows for binding of DNA at enhancer sequences
3. This promotes RNA polymerase recruitment to promoter regions

Question 7

How do GPCRs work?

Answer 7

G-Protein Coupled Receptors are 7 transmembrane proteins. In the intracellular domain, they bind to G proteins - weak GTPases composed of 3 subunits, α,β,γ. α subunit is bound to GTP when active and GDP when inactive. When GPCR binds to ligand, GPCR undergoes conformational change in shape causing G-proteins become activated and relay the signal causing a cascade response

Ligands are highly diverse: photons, odours, hormones, neurotransmitters, amino acid residues.

• Sometimes 1 signalling molecule can activate multiple GPCR to trigger specific pathways

e. g
1. adrenalin binds to adrenergic receptor (GPCR) causing it to become activated and undergo conformational change in shape
2. Alpha subunit exchanges GTP for GDP and dissociated from beta and gamma, binds to adenylate cyclase
3. adenylate cyclase converts ATP to cAMP
4. cAMP is second messenger which binds to protein kinase A and activates it
5. Protein Kinase A phosphorylates and moderates activity in proteins

• amplification of molecules

Question 8

What are bio switches?

Answer 8

Bio switches

• amplifications
  
  • small signals (ligands) lead to lots of cAMP
• Short duration signals
  
  • Gives ability to turn signalling events on and off
  • PKA activates phosphodiesterase which rapidly removes cAMP → AMP (inactive second messenger)
  e.g
• cAMP
• Phosphorylation by protein kinase
• phosphorylation event - add phosphate from ATP to tyrosine, threonine/serine

Question 9

What are receptor tyrosine kinase (RTK)?

Answer 9

Receptor Tyrosine Kinase (RTK) = Specific kinase that transfers phosphate to the amino acid tyrosine

• are single pass enzyme coupled transmembrane receptors
  
  • only cross transmembrane once

extracellular region = cysteine rich intracellular region = tyrosine kinase domain

• act as ligand modulated protein kinases
• are dimeric when active
• respond to e.g epidermal growth factor, insulin, often peptides

e. g epidermal growth factor (EGF)
- too big to pass through membrane so has to interact with a membrane bound receptor

1. EGF binds to monomeric RTK which activates it causing dimerisation (2 adjacent RTK come together)
2. Triggers phosphorylation of neighbouring RTK
3. Phosphorylated RTK binds to adapter protein which binds to Ras-GEF - exchanges GDP for GTP and Ras (monomeric G protein)
4. Ras GTP (activated form) binds and activates MAPKKK (kinase, kinase, kinase) which then phosphorylates and activates MAPKK, which then p and a MAPK which then p and a Myc (transcription factor)
5. Activated Myc binds to enhancer box and activates transcription inside the nucleus

• *SIGNAL TURNED OFF:**
• through dephosphorylation events
• also through intrinsic GTPase activity of Ras - can be sped up by Ras GAP (stimulating protein)