MR 6

Question 1

Discuss the principles of communication between cells via chemicals messengers in the paracrine, endocrine and nervous systems.

Answer 1

Paracrine - signalling cell releases chemical messengers that exert their effect on adjacent cells.

Endocrine - chemical messenger enter the blood and exert their effect at a site that is distant to the site of origin.

Neurotransmitter - released from nerve axons, and exert their effect on the target cell.

Question 2

Briefly describe membrane bound receptors with integral ion channels.
Name some of these receptors, with the ion that they conduct.

Answer 2

These are receptors that have an intrinsic ion channel, which allows fast transmission. The signal is transduced into an electrical activity at the membrane.
Eg
NAChR - pentameric which conducts Na, K and Ca.

Glutamate- conducts Ca. During brain injury, this is activated and Ca can flow into cells which further damages the tissue

GABA - allows flow of Cl-

Question 3

Discuss membrane bound receptors with integral enzyme activity.

Answer 3

These are receptors that have an enzyme within the protein structure of the receptor, which is activated upon ligand binding.

• tyrosine residues on cytoplasmic domains become phosphorylated
• these residues are then recognised by either enzymes or signal transducing proteins
• effector enzymes become activated upon association with the phosphorylated residues. (Allosteric activation)
• hence the receptor binding signal is transduced into an intracellular event.

Question 4

In what way can the length of GPCR activation be thought of as a ‘clock’

Answer 4

Ga has an intrinsic GTPase which will hydrolyse the GTP back into GDP, so the affinity for Ga subunit for the BY subunit increases again and they associate again - this inactivated the receptor. The length of time taken for the GTP to be hydrolysed is the length of activation.

Question 5

Discuss membrane bound receptors with no integral enzyme of channel activity.

Answer 5

• coupled to effector molecules via GPCRs.
• effectors can be enzymes such as Adenylyl cyclase or ion channels
• the Ga and BY subunit dissociate when GDP is replaced by GTP, as when GTP is bound to Ga, the affinity for BY decreases hugely. (See session 7).
• this then transduces the signal to an enzyme or ion channel.

Question 6

Describe intracellular receptors.

Answer 6

• located within the cell so ligand must cross the hydrophobic bilayer
• when unbound, the receptor is stabilised by chaperone/HSPs
• when ligand binds, receptor is translocated from chaperone to nucleus
• within the nucleus, gene expression is affected
• effect of ligand binding takes longer as it has to affect the protein synthesis.

Question 7

Describe the process of receptor mediated endocytosis (RME) using the uptake of cholesterol as an example.

Answer 7

-cholesterol needing cells synthesise receptors that recognise ApoB
-ApoB receptors located over coated pits (clathrin coated)
-when apoB binds to receptor, that part of coated pit pinches off, to form coated vesicles.
-clathrin coat is removed, and the uncoated vesicle fuses with endosomes, at pH 5-6. At this pH, the LDL-receptor dissociates.
-endosome is called Compartment for Uncoupling Receptor-Ligand aka CURL
-receptor sequestered to an area of the CURL that pinches off and replaces receptor back into the membrane
-endosome fuses with lysozyme that hydrolyses the cholesterol esters and releases it into the cytoplasm.
-

Question 8

In the RME of cholesterol, comment on the fate of the ligand and receptor.

Answer 8

Receptor recycled, ligand is degraded.

Question 9

How can RME contribute to the uptake of metabolites. (Eg Fe3+)

Answer 9

• 2Fe3+ molecules bind to apotransferrin, forming transferrin
• transferrin binds to its receptor and its internalised(like LDL)
• apotransferrin cannot bind to the receptor alone
• transferrin reaches endosome where the Fe3+ is released
• apotransferrin and receptor dissociate from each other in the CURL and both are then recycled.

Question 10

How can RME control the receptor number at the cell surface?

Answer 10

Using insulin as an example:

• most receptors are located over coated pits
• when insulin is bound to receptors, the receptors are located in coated pits
• in the endosome, the insulin remains bound to the receptor, and both are targeted to the lysozyme for degradation
• this reduces the number of insulin receptors so it desensitises the cell the high levels of insulin
• both receptor and ligand degraded.

Question 11

How does RME allow the entry of membrane coated viruses?

Answer 11

• viruses internalised via endocytosis
• virus is released into the cell after fusion with the endosome
• free to be translated at take over cell machinery.

Question 12

Define the following terms:
Acceptor
Ligand
Agonist
Antagonist

Answer 12

Acceptor
- if the basic function of a ‘receptor’ can occur without the ligand being bound, then this is termed an acceptor.

Ligand
- a small molecule that binds specifically to a receptor

Agonist
- produces activation of a receptor

Antagonist
- when bound, it prevents the receptor from becoming activated. IT DOES NOT CAUSE INACTIVATION OF THE RECEPTOR.