Cell signalling

Question 1

Why do we need cell signalling?

Answer 1

1. To process information (e.g auditory signal)
2. Self-preservation (e.g reflex following painful input)
3. Voluntary movement
4. Homeostasis

Question 2

What are the two main systems within the body that provide these lines of communication?

Answer 2

1. Nerve fibres of the central and peripheral nervous system (rapid and instantaneous).
2. The blood vessels of the cardiovascular system (slower more versatile regulations).

Question 3

How do nerve fibres carry out cellular communication?

Answer 3

• Through neurotransmission between a presynaptic axon terminal and a postsynaptic cell.
• Happens as follows:
  
  1. Propagation of action potential
  2. Neurotransmitter released from vesicle into the synaptic cleft
  3. Activation of the postsynaptic receptors

Question 4

What events take place during propagation of an action potential in the presynaptic axon?

Answer 4

• Action potential is formed by voltage-gated Na+ ion channels opening and result in an influx of Na+ ions.
• This causes the membrane to depolarise and the action potential ‘moves along’ the neurone.
• Then voltage-gated K+ channels open and result in an efflux of K+ ions.
• This causes the membrane to repolarise
• These events lead to the propagation of action potential which generates a bioelectric current.

Question 5

What event takes place when the action potential arrives at the end of the presynaptic terminal?

Answer 5

• Voltage-gated Ca2+ ion channels open resulting in a Ca2+ influx.
• This results in Ca2+ binding to vesicles at the nerve terminal
• Which promotes the exocytosis of these vesicle containing neurotransmitters into the synaptic cleft.

Question 6

What events take place after the release of neurotransmitters into the synaptic cleft?

Answer 6

• The neurotransmitters bind to the receptors in the postsynaptic membrane.
• These receptors then modulate the postsynaptic cell activity by either depolarising or hyperpolarising the postsynaptic membrane.

Question 7

What are the 4 main modes of hormonal communication?

Answer 7

• Endocrine
• Paracrine
• Communication between membrane receptors
• Autocrine communication

Question 8

What is endocrine signalling?

Answer 8

• It is when a hormone travels within a blood vessel to act on a distant target cell.
• Examples of endocrine signalling are:
  
  • Insulin production by the pancreas which acts on the liver, muscle cells and adipose tissue
  • Adrenaline production by the adrenal glands which act on the trachea.

Question 9

Describe the physiological response to hypoglycaemia and suggest what mode of hormonal communication it is.

Answer 9

• Example of endocrine communication.
• Includes the following processes:
  
  1. Glucagon production (secreted by α-cells of islets of Langerhans in the pancreas).
  2. Glucagon travels out of the pancreas into the blood vessels.
  3. Glucagon stimulates glycogenolysis and glucogenesis within the liver which increases blood glucose levels.

Question 10

What is paracrine signalling?

Answer 10

• Paracrine signalling is defined as when a hormone acts on an adjacent cell.
• Examples of paracrine signalling include:
  
  • Production of nitric oxide by endothelial cells in blood vessels to cause vaso-dilation. E.g when people go into septic shock.
  • Osteoclast activating factors produced by adjacent osteoblasts in the process of bone formation.

Question 11

Describe the physiological response to hyperglycaemia and suggest what mode of hormonal communication it is.

Answer 11

• Example of paracrine communication
• Includes the following processes:
  
  • Increased blood glucose results in insulin secretion by the β-cells of the Islets of Langerhans.
  • Insulin has paracrine effects like inhibiting glucagon secretion by acting on the adjacent α-cells.
  • Insulin also has an endocrine effect by acting on the liver to promote glucose uptake.

Question 12

What are the examples of signalling between membrane attached proteins?

Answer 12

1. Blood-borne viruses:
   
   • Blood-borne virus (e.g Hep C) detected within bloodstream by an antigen-presenting cell (APC).
   • APC digests pathogen and expresses major histocompatibility (MHC) class II molecules on the surface.
   • MHC class II molecules interact with T cell receptor on circulating T lymphocytes.
2. Other examples:
   
   • HIV GP120 glycoprotein attaching on CD4 receptors on T lymphocytes
   • Bacterial cell wall components bind to toll-like receptors on haematopoietic cells.

Question 13

What is an example of autocrine signalling?

Answer 13

• Activation of T-cells:
  
  • The activated T-cell receptor will initiate a cascade of reactions within T-cell.
  • Activated T-cell expresses the interleukin 2 (IL-2) receptor on the surface.
  • The activated T-cell then secretes IL-2 which
    
    • binds to IL-2 receptor on the same cell
    • binds to Il-2 receptor on adjacent activated T-cells.
• Other examples include (not imp):
  
  • Acetylcholine acts on presynaptic M2 muscarinic receptors
  • When growth factors (TGFβ) from tumour cells act on themselves to cause mitogenesis (induction of mitosis).

Question 14

What can you also refer to the chemical messages or molecules as?

Answer 14

They can also be referred to as ligands since they exert their effects through binding to the receptors.

Question 15

What usually happens following a ligand binding to a receptor?

Answer 15

• Surface receptors are usually proteins that bind to ligands to get activated and upon activation elicit an effect within the cell.
• The intracellular effect evoked by this occupied receptor usually arises as a result of a second messenger.
• A secondary messenger is a chemical messenger separate from the receptor or the ligand.

Question 16

What are the four distinct categories of receptors?

Answer 16

1. Ligand-gated ion channel receptors
2. G protein-coupled receptors
3. Enzyme-linked receptors
4. Intracellular receptors

Question 17

Describe the structure of ligand-gated ion receptors (ionotropic receptors).

Answer 17

• Transmembrane receptors expressed on cell membranes with a central pore incorporated into their quaternary structures.

Question 18

How does an ionotropic receptor work?

Answer 18

• An appropriate ligand binds to the ‘ligand-binding domain’ on the external surface of the protein.
• This results in a change in conformation of the channel proteins which opens a pore that spans the cell membrane.
• The pore allows ions to move in or out of the cell according to their respective concentration gradients (movement down the gradient).

Question 19

What are some examples of ionotropic receptors?

Answer 19

• Nictotinic acetylcholine (ACh) receptors on muscle and nerve cells (muscle contraction and cognitive enhancement). Ligand = ACh
• Gamma-Aminobutyric Acid a receptor (GABBA_a) in nerve cells (inhibition of neuronal activity). Ligand = GABA
• N-methyl-D-aspartic acid (NMDA) in nerve cells (synaptic plasticity and memory formation). Ligand = Glutamate.
• 5-hydroxy tryptamine 5-HT₃ in nerve cells (anxiety and emesis or vomiting). Ligand = 5-HT

Question 20

Describe the structure of G-coupled receptors.

Answer 20

• Also known as 7-transmembrane receptors because the channel protein crosses the membrane 7 times.
• Linked to intracellular G protein complex.

Question 21

What is the G protein complex and what is it composed of?

Answer 21

• It is a heterotrimeric protein that works with a 7-TM receptor.
• An alpha subunit, a beta-gamma subunit and an associated GDP molecule.

Question 22

Describe the variation in Gα subunits and its implications.

Answer 22

• Gα variation can be broadly separated into three categories which are associated with alternative signal transduction pathways:

Question 23

Describe the process involved in G protein activation.

Answer 23

1. In the resting state, the complex consists of the G alpha subunit, G beta-gamma subunit and an associated GDP molecule which are in close proximity to the receptor.
2. Ligand binding causes a conformational change in the 7-TM resulting in the G protein complex associating with the receptor
3. The GDP molecule is then either phosphorylated to a GTP molecule or exchanged for a GTP molecule.
4. Then the G alpha dissociates from the G beta-gamma subunit.
5. Both of the subunits can act as second messengers and bind to their target proteins.
6. When the ligand dissociates from the receptor, internal GTPase on the G alpha subunit hydrolysis GTP to GDP.
7. The G alpha and G beta gamma subunits re-associate and are once again available to the receptor.

Question 24

What are some examples of G-protein coupled receptors?

Answer 24

• Over a 1000 different G protein-coupled receptors encoded in the human genome.

Question 25

Describe the structure of enzyme-linked receptors

Answer 25

• Membrane spanning receptors with an external and internal component.
• Have one transmembrane domain, which has the ligand-binding domain on the outside and specialised enzymes (usually tyrosine kinase enzymes) on the inside.

Question 26

Briefly outline how enzyme-linked receptors work.

Answer 26

• Do not ordinarily work alone and require clustering of more than one receptor protein to activate the intracellular enzyme.
• Once activated the intracellular enzymes trigger a signalling cascade within the cell.

Question 27

Describe the processes linked in enzyme-linked receptor activation.

Answer 27

1. Ligand binding results in receptors clustering.
2. Receptor clustering activates enzyme activity within the cytoplasmic domain.
3. The enzymes phosphorylate the receptor.
4. This phosphorylation leads to the binding of signalling proteins to the cytoplasmic domain.
5. These signalling proteins recruit other signalling proteins and a signal is generated within the cell.
6. The signal is terminated when a phosphatase dephosphorylates the receptor.

Question 28

What are some examples of enzyme-linked receptors?

Answer 28

Question 29

What are intracellular receptors?

Answer 29

• They are intracellular transcription factors acted upon by hormones that are membrane-permeable (i.e. hydrophobic, lipophilic).
• There are type I and type II intracellular receptors.

Question 30

How is an intracellular type I receptor activated?

Answer 30

• They are located within the cytosolic compartment and associated with chaperone molecules (normally heat shock proteins, hsp).
• Once the hormone binds to the receptor, the hsp molecule dissociates allowing the hormone-receptor complex to form a homodimer with another identical hormone-receptor complex.
• The homodimer translocates into the nucleus where it binds to DNA and acts as a transcription factor.

Question 31

How is an intracellular type II receptor activated?

Answer 31

• Located within the nucleus of a cell and are often already bound to DNA.
• Binding of the hormone ligand to the receptor usually results in direct transcriptional regulation by the activated hormone-receptor complex.

Question 32

What are some examples of intracellular receptors?

Answer 32