Response

Question 1

Receptor definition

Answer 1

Cellular macromolecule that recognise and respond to endogenous chemical signals

Question 2

Three types of receptors

Answer 2

Ligand-gated- inotropic receptors

G-protein coupled receptors- metabotropic receptors

kinase linked receptors

Question 3

inotropic v metabotropic meanings

Answer 3

Inotropic respond to a single ligand binding, whereas metabotropic function using second messenger systems, with the metabotropic receptor being indirectly linked to the ion channel

Question 4

Role of each receptor

Answer 4

Ligand gated- changes in membrane potential or ion concentration within cell

G-protein coupled- protein phosphorylation, calcium release, change in excitability

kinase linked- protein and receptor phosphorylation

Question 5

Time scale of each receptor

Answer 5

ligand gated- millisecond

G protein coupled- seconds

kinase linked - hours

Question 6

What is a receptor sub type? + example

Answer 6

Receptors with differences in their primary structure which affects their affinity to the drug agent. Different subtypes appear in different regions of the body. e.g different subtypes of nAChR in the brain and skeletal muscle

Question 7

GPCR structure

Answer 7

Single polypeptide chain, 350-400 residues. Seven transmembrane alpha helices . Two extracellular binding sites- one N terminal and another further within membrane.

G protein comprised of three subunits: alpha, beta and gamma

Question 8

Examples of G protein coupled receptors

Answer 8

Muscarinic AChRs, adrenoreceptors, dopamine receptors, 5-HT serotonin receptors, GABA

Question 9

What binds to each extracellular domain?

Answer 9

Small molecules such as noradrenaline or ACh bind to -ligand binding domain buried in the cleft between alpha helical segments. Peptide ligands bind more superficially to the extracellular loops.

Question 10

What is a second messenger system?

Answer 10

Second messengers are intracellular signal molecules that are released by the cell in response to extracellular signals (the primary messenger)

Question 11

How do second messengers amplify a signal?

Answer 11

There are few primary messengers compared to the large number of receptors, so many secondary messengers are released which can target even more receptors.

A single agonist-receptor complex can activate several G protein molecules in turn.

Question 12

Simple mechanisms of GPCRs

Answer 12

1. G protein binds to an agonist occupied receptor, which has undergone a conformational change to reveal a G protein binding site.
2. alpha subunit binds to GTP and dissociates
3. Alpha unit free to bind to an effector to activate
4. GTP molecule hydrolysed to GDP by the inherent GTPase activity of the alpha subunit, which allows the alpha subunit to recombine with beta gamma

Question 13

How are the alpha, beta and gamma sub units bound?

Answer 13

In resting state, the beta and gamma sub units are covalently bound together and the gamma subunit is anchored to the membrane through a fatty acid chain, known as prenylation.

alpha, beta, gamma trimer may or may not be precoupled with receptor

Question 14

Four main classes of G protein

Answer 14

Gs, Gi, Go and Gq

Question 15

How do the G proteins mainly differ?

Answer 15

Different alpha sub unit

Question 16

Two main targets for G proteins

Answer 16

Adenylate Cyclase and Phospholipase C

Question 17

what is cAMP?

Answer 17

a nucleotide synthesised within the cell from ATP by the membrane bound enzyme adenylate cyclase.

Question 18

Cyclic AMP function

Answer 18

Regulate many aspects of cellular function such as enzymes involved in energy metabolism, cell division and cell differentiation, ion transport, ion channels and the contractile proteins in smooth muscle

Question 19

How do these processes begin?

Answer 19

By activating AMP dependent protein kinases, such as protein kinase A

Question 20

protein kinase function

Answer 20

Regulate the function of intracellular proteins by controlling protein phosphorylation. PKa phosphorylates serves/thy residues.

Question 21

Control of adenyl cyclase stages

Answer 21

1. adrenaline binds to beta adrenoreceptor which is a Gs protein coupled receptor
2. alpha subunit from Gs protein Coupled Receptor binds to adenyl cyclase which thus becomes activated
3. activated adenylate cyclase catalyses the conversion of ATP to cAMP
4. 2 cAMP molecules bind to each of the 2 binding sites on PKA.
5. PKa undergoes a conformational change and loses two subunits, revealing two catalytic ones

Question 22

How is adenylate cyclase inhibited?

Answer 22

Adrenaline binds to Gi protein coupled receptor. Beta gamma unit thought to inhibit the enzyme

Question 23

How is the pathway often inhibited?

Answer 23

Phosphodiesterase converts cAMP to AMP by hydrolysis.

Question 24

What are phosphodiesterase inhibitors + examples + benefits?

Answer 24

Methylated xanthines such as caffeine, which act as competitive inhibitors for phosphodiesterase, thus increasing the cAMP concentration in the cell.

Question 25

Two ways in which intracellular calcium is raised

Answer 25

1. release of calcium from intracellular stores

2. opening calcium channels in cell membrane

Question 26

Another way to name the process of releasing calcium from intracellular stores

Answer 26

phosphatidylinositol pathway

Question 27

Explain stages of phosphatidylinositol pathway

Answer 27

1. Extracellular ligand binds to the Gq protein coupled receptor.
2. alpha subunit binds to phospholipase C thus activating it
3. The lipase hydrolyses PIP2 into inositol IP3 and diacylglycerol DAG.
4. IP3 binds to ligand gated calcium channels on the sarcoplasmic reticulum, leading to calcium loss from the cell
5. DAG activates Protein Kinase C which has many cellular activities

Question 28

Where does PKc become activated + why?

Answer 28

DAG is very lipophilic so remains in the cell membrane, thus this is where it bind to PKC and activates it.

Question 29

What is calmodulin?

Answer 29

Dumbell shaped protein with a globular domain at each end, each with two calcium binding sites.

When all calcium binds the molecule undergoes a conformational change and becomes sticky, that lures proteins into association and thus can regulate their function.

Question 30

How is calmodulin related to phosphatidylinositol pathway?

Answer 30

Calcium released cooperates with DAG in activating PKC which activates the CaM pathway in which calmodulin binds to calcium ions and then activates CaM kinase II

Question 31

Calmodulin role in contraction

Answer 31

Binds to myosin light chain kinase which phosphorylates the myosin head, enabling it to form crosslinks in smooth muscle

Question 32

How are calcium levels lowered?

Answer 32

1. extruded from the cell in exchange for sodium in the sodium calcium anti porter- sodiums removed for one calcium
2. SERCA pump moves calcium back into SER

Question 33

What form of receptor is this example of GqPCR?

Answer 33

alpha 1 adrenoreceptor

Question 34

Function of gap junctions

Answer 34

Enable second messengers to move between cells with ease and rapidly, increasing amplification of the signal

Question 35

What is tachyphylaxis?

Answer 35

A form of drug desensitisation. Receptors become less responsive to agonists

Question 36

How do kinase-linked receptors work?

Answer 36

1. ligand binds to N terminal extracellular binding domain

2. undergoes conformational change so that intracellular catalytic domain is now activated

Question 37

Examples of kinase linked receptors

Answer 37

Receptor tyrosine kinase- binds to epidermal growth factor