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What is paracrine signalling?

Signalling between cells by using a local mediator that travels in the interstitial fluid to reach its target cell.


What is endocrine signalling?

Signalling using a hormone that travels in the blood to its target cell - can travel long distances.


What is synaptic signalling?

Signalling from pre-synaptic to post-synaptic neurone by the release of neurotransmitters into the synaptic cleft.


Name three subdivision of signalling molecules. Why does this classification, alothough useful, no longer hold?

1. Local chemical mediators
2. Hormones
3. Neurotransmitters
Can't classify all molecules into one group - may occur in two groups.


What is the difference between cell surface and intracellular receptors?

The majority of receptors are found on the cell-surface (PM) and bind hydrophilic signalling molecules. Intracellular receptors bind to small hydrophobic molecules inside the cell. These molecules are transported extracellularly by carrier proteins and are able to diffuse through the PM.


What is a receptor?

A molecule that recognises specifically a second molecule (ligand) or family of molecules and which in response to ligand binding brings about regulation of a cellular process.
NB: In the unbound state a receptor is functionally silent.


What is a ligand?

Any molecule that specifically binds to a receptor site. It may produce activation of a receptor, in which case it is an agonist. Or it may combine with the receptor site without causing activation in which case it is an antagonist (because it opposes the action of an agonist).


What is the mechanism of action of an antagonist?

They bind to receptor sites without causing activation. They oppose the action of agonists because they cannot bind to the receptor site whilst the antagonist is bound.


List some roles of receptors in cellular physiology:

1. Signalling by hormones/ local chemical mediators
2. Neurotransmission
3. Cellular delivery - targeting of therapeutics
4. Control of gene expression
5. Cell adhesion
6. Modulation of immune response
7. Sorting of intracellular proteins (e.g. KDEL)
8. Release of intracellular stores (organelle receptors)


What is the function of the KDEL sequence?

Proteins with this sequence are target to the ER - this includes their retrograde transport from the golgi.


How do the binding affinities of receptors and enzymes compare?

Affinity of ligand binding at receptor sites is generally much higher than binding of substrates and allosteric regulators to enzyme sites.


How are receptors classified?

1. According to the ligand which they bind e.g. nicotinic acetylcholine receptor is activated by nicotine (agonist) as well as ACh.
2. Sub-classified by affinity of a series of antagonists e.g. M1 is blocked by the same antagonists as M2 and M3 but Pirenzipine is the most potent.


What is the difference between a receptor and an acceptor?

1. At rest - a receptor is silent but an acceptor is operating
2. Agonist binding - stimulates a biological response in a receptor but produces no response in an acceptor.


How does methotrexate work? What is it used for?

It inhibits folic acid reductase which DNA synthesis (purine and pyrimidine synthesis) and cellular replication. It is therefore used as an anti-cancer drug.


Discuss different mechanisms of signal transduction

1. Membrane-bound receptors with integral ion channels
2. Membrane-bound receptors with integral enzyme activity
3. Membrane-bound receptors which couple to effector through transducing proteins
4. Intracellular receptors


What is signal transduction?

The transmission of molecular signals from a cell's exterior to its interior.


What ions does the membrane-bound receptor with integral ion channels - nAChR - allow through?

Na+, K+ and Ca2+ (mainly Na+)


What ions does the membrane-bound receptor with integral ion channels - GABA (gamma amino butyric acid) receptor - allow through?



What ions does the membrane-bound receptor with integral ion channels - glycine receptor - allow through?



What ions does the membrane-bound receptors with integral ion channels - glutamate receptors (such as NMDA, kainate and AMPA) - allow through?



What ions does the membrane-bound receptor with integral ion channels - IP3 receptor - allow through?

Ca2+ from the ER.


What are the excitatory/ inhibitory effects of GABA and glycine receptors?

They cause an influx of Cl- and therefore hyperpolarise the cell -> inhibition of action potentials.


Describe the structure of nAChR

1. Pentameric (2x alpha, 1x beta, gamma and delta)
2. 2x alpha subunits contain a receptor for ACh each


Describe the structure of a 'classical' ligand-gated ion channel?

1. Extracellular N- and C-terminus
2. N-terminus contains the ligand binding domain
3. 2nd membrane domain lines the channel (present in each subunit)


Describe the structure of a membrane-bound receptor with integral enzyme activity

1. Dimer
2. N-terminal domains are the binding domains (on both subunits)
3. C-terminal domains are the catalytic domains (on both subunits)
4. Binding of ligand causes conformational change which activates catalytic domains on the inside of the cell.


How does the membrane-bound receptor with integral enzyme activity - atrial natriuretic peptide (ANP) receptor - work?

It is linked directly with guanylyl cyclase which converts GTP to cGMP. cGMP then goes on the be a second messenger.


How does the membrane-bound receptor with integral enzyme activity - growth factor receptors (e.g. insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) - work?

Linked directly to tyrosine kinase - becuase they all want to illicit the same response = growth.


Explain the mechanism of signalling via tyrosine kinase-linked receptors:

1. Binding of receptor agonist causes autophosphorylation by each of the intracellular domains of the dimer
2. Phosphorylated sites become the docking sites for enzymes/ transducing proteins containing the SH2 domain


What do SH2 regions on proteins always bind to?

Phosphorylated tyrosine residues.


What type of receptor are insulin receptors?

Tyrosine kinase-linked receptors