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0

How may chemical signalling be classified?

According to their functions:

Hormones (signalling between cells in different tissues via the circulation)

Neurotransmitters (signalling at specialised cell junctions in the nervous system, synapses)

Local chemical mediators (signalling between adjacent cells in the same tissue)

Note: a single molecule may fall into more than one of these categories depending on where it is synthesised and released and its site of action.

1

What is a receptor?

Molecule that specifically recognises a second molecule (ligand) or family of molecules and in response to ligand binding, brings about regulation of a cellular process.

In the unbound state a receptor is functionally silent.

2

Describe the affinity of ligand binding at receptor sites

The affinity of ligand binding at receptor sites is generally much higher than binding of substrates to enzyme sites.

This is as ligands may only be present in very small concentrations.

3

Give some examples of the role of receptors in cellular physiology

Examples include:

Signalling by hormones/local chemical mediators

Neurotransmission

Cellular delivery

Control of gene expression

Cell adhesion

Modulation of the immune response

Sorting of intracellular proteins

Release of intracellular calcium stores

4

What is an Acceptor?

Many molecules whose activities are modified by the binding of small chemicals, including drugs, are not strictly receptors.

If their basic function can be carried out without the interaction of a ligand, then they are not, by definition a receptor.

5

What is a ligand? And what are agonists and antagonists?

Any molecule that binds specifically to a receptor site.

If the binding of the ligand produces activation of a receptor by changing its conformation in some way, it is an agonist.

If a receptor binds without causing activation on the receptor, it is an antagonist. It opposes the actions of an agonist. Once it binds to receptor, the receptor cannot be bound by an agonist, preventing it from being activated.

6

What is a partial agonist?

Agonist which stimulates a receptor but unable to elicit the maximum cell response possible

7

Are Dihydrofolate Reductase and Voltage-Gated Sodium Channels Acceptors or Receptors?

Dihydrofolate reductase is inhibited by binding of the drug methotrexate and is sometimes referred to as the methotrexate receptor, this enzyme operates normally in the absence of methotrexate - it is an Acceptor as it operates in absence of ligand and ligand binding alone produces no response.

Voltage - Gated Na+ channels can be modulated by binding of local anaesthetic agents and a variety of neurotoxicity molecules but it opens in the absence of any signalling molecule so it also an acceptor.

8

What happens when the signalling molecule is hydrophilic?

The signal recognition site of the receptor must be present on the extracellular face of the cell surface.

Interaction of the signalling molecule with its specific receptor must then result in the activation of a cellular process.

Hence signal transduction is needed as hydrophilic signalling molecules cannot pass through cell membranes.

Signal transduction is brought about by the extracellular receptor at the cell surface transmitting the signal into the cell.

9

What happens when the signalling molecule is hydrophobic?

It will be able to pass through the cell membrane (through the lipid bilayer) by diffusion but an intracellular receptor is still required to transduce the signal into a cellular response

e.g. Steroid and thyroid hormones.

10

How can receptors be classified according to the specific physiological signalling molecule (agonist) that they recognise?

E.g. Receptor type: nicotinic (agonist: nicotine) and muscarinic (agonist: Muscarine)

Further subclassification is often made on the basis of their ability to be selectively activated by agonist molecules and sub-classification is also often made on the basis of the affinity (a measure of tightness of binding) of a series of antagonists .

11

What are the similarities between receptor binding sites and the active sites and regulatory sites of enzymes?

Binding is specific - specificity is governed by shape of the binding cleft in the receptor or enzyme site.

Specificity of binding confers specificity to the regulation of processes which in receptors are involved of the specificity of substrate of an enzyme.

Binding to both receptors and enzyme is most often reversible.

Ligand binding to receptor and regulator binding to enzyme allosteric sites both induce a conformational change and a change in the activity of the molecule (ligand and substrate molecules may also 'induce a fit')

There is no chemical modification of ligand in receptor binding sites or enzyme regulatory sites.

12

What are the differences between receptor binding sites and the active sites and regulatory sites of enzymes?

The affinity of ligand binding at receptor sites is generally higher than the binding of substrates and regulators to enzyme sites.

The ligand bound to a receptor site is not modified chemically whereas substrate bound in an enzyme active site is modified in a chemical reaction catalysed by the active site.

13

What are the common mechanisms to transduce an extracellular hydrophilic signal into an intracellular event?

1. Membrane-bound receptors with integral ion channels.

2. Membrane-bound receptors with integral enzyme activity

3. Membrane- bound receptors which couple to effectors through transducing proteins.

4. Intracellular receptors for hydrophobic ligands.

14

Describe how Membrane-bound receptors with integral ion channels work

Agonist binding to ligand-gated ion channel results in a change in conformation and opening of a gated channel which permits the flow of ions down an electrochemical gradient.

This transduces the signal into an electrical event at the plasma membrane .

15

Describe the subunit structure of the 'classical' ligand gated ion channel family

They have similar pentameteric subunits.

The subunits have four transmembrane domains e.g. nACh receptors, gamma aminobutyric acid (GABA(A)R), Glycine receptors

One of the four transmembrane domains forms the lining to the channel pore (M2)

 Receptors are composed of five homologous, but not identical polypeptide subunits

Agonist binding occurs in the extracellular N-terminal domain of subunits containing a binding site

16

Are there non-classical ligand ion channels?

Yes, other structurally distinct ligand-gated ion channel families can also be present in cells e.g ATP-sensitive K+ channels, Ryanodine receptors, IP3 receptor, P2x-purinoceptor (ATP)

17

Describe Membrane-bound receptors with integral enzyme activity

Agonist binding to the extracellular domain of these receptors causes a conformational change which activates an intrinsic enzyme activity contained within the protein structure of the receptor e.g. Tyrosine kinase-linked receptors, guanylyl cyclase-linked receptors.

Examples include growth factor receptors such as receptors for insulin, epidermal growth (EGF) and platelet derived growth factor (PDGF) linked directly to tyrosine kinase.

18

Explain Tyrosine Kinase Linked Receptors

Binding of ligand to extracellular binding sites activates a protein kinase activity in the cytoplasmic domain of the receptor protein, which autophosphorylates (catalyses the transfer of a phosphate group from ATP on its own structure) tyrosine residues on the cytoplasmic domain of the receptor.

19

What happens to the phosphorylated receptor tyrosine residues?

Recognised either by transducing proteins e.g. Insulin receptor substrate-1 (IRS-1), or directly by enzymes containing the phospho tyrosine recognition sites, Src-homology-2 (SH2 domains).

On association with receptor or transducing protein, effector enzymes become activated allosterically or possibly by tyrosine phosphorylation by the receptor kinase, thus transducing the message into an intracellular chemical event.

20

What does a transducer presenting with multiple tyrosine residues mean?

The multiple tyrosine residues are phosphorylated after ligand binding and can recruit many different effectors at once.

Activation of 1 receptor --> multiple responses. Often activates a cascade.

21

Describe how membrane-bound receptors which couple to effectors through transducing proteins proteins work

No integral enzyme activity or integral ion channels.

Seven transmembrane domain receptors (7TMDR) couple to effector molecules via transducing molecule, a GTP-binding regulatory protein (G-Protein).

This family of receptors is also known as the GPCR family.

Effectors may be enzymes (e.g. Adenylyl cyclase) or ion channels (e.g. Ca2+, K+)

Receptor binding results in a conformational change which activates GDP/GTP exchange in GTP-binding regulatory proteins which transduce the message onto an enzyme or ion channel in the membrane.

22

A wide variety of extracellular signalling molecules utilise specific 7TMD receptors so this structure is common. Give some examples

mAChR, dopamine receptors, adrenoceptors, opioid receptors,peptide receptors, light receptors, smell and taste receptors.

Often a number of different types of G-protein receptors exist for a particular agonist e.g. M1-M5 mAChRs

23

What is integrated signalling?

Often, separate G-protein coupled receptors will act simultaneously to both stimulate/inhibit the effector.

This is integrated signalling and the two inputs combine to produce a measured effect.

24

Explain how Intracellular receptors for hydrophobic ligands work

Hydrophobic ligands (e.g. Steroid hormones, thyroid hormones) pass through the plasma membrane and bind to monomeric receptors in the cytoplasm of nucleus.

In the resting state these receptors are stabilized by association with heat shock or chaperone proteins.

The activated receptor dissociates from the chaperone protein and translocates to the nucleus where it binds to control regions in DNA defined by specific sequences, thereby regulating gene expression.

Compared to extracellular receptors that act through ion channels or enzymes, the action of intracellular receptors is relatively slow as they are dependent on transcription and translation.

25

Explain Amplification in Cellular Signalling

The concentration of many extracellular signalling molecules is very low.

For all signalling mechanisms there is the possibility of molecular amplification e.g., by stimulating the activity of an enzyme, the binding of a chemical signal molecule to a single receptor can cause the modification of hundreds or thousands of substrate molecules.

A cascade of such catalytic events can produce further amplification.

26

Cellular Activation and Inhibition depends on the receptor. Explain about cellular activation and inhibition in cardiac pacemaker cells

Noradrenaline --> B1-adrenoceptors produces increased Heart Rate

Acetylcholine --> M2 muscarinic receptors produces slowing of Heart Rate

27

Cellular Activation and Inhibition depends on the receptor. Explain about cellular activation and inhibition in hepatocytes

Insulin stimulates the synthesis of glycogen from glucose while glucagon stimulates glycogen breakdown to glucose

28

What are the 3 Processes of Membrane Internalisation? - since cell membranes do not become excessively ruffled, there must be an opposite movement of cell membrane back into the cell by endocytosis after release of vesicle contents by exocytosis)

Phagocytosis

Pinocytosis

Receptor-mediated Endocytosis

29

Describe Phagocytosis

Found only in specialised cells e.g. Macrophages and neutrophils.

In response to binding of a particle to receptors in the plasma membrane, the cell extends pseudopods which permit further receptor interactions and membrane invagination/particle invagination via a membrane-zippering mechanism.

Internalized Phagosomes fuse with lysosomes to fuse phagolysosomes in which the particulate material is degraded.

This process permits the clearance of damaged cellular materials and invading organisms for destruction.