Lecture 4 - Receptor mechanism II

Question 1

GPCR (8)

Answer 1

1 single protein
7 transmembrane proteins
e.g. B adrenoreceptors in the heart 
N terminal - ligand binding site
C - terminal G protein binding site
Signal transduction mechanism
Response seconds to minutes - slower than ligand-gated
4 main families based on the structure

Question 2

What are G-proteins? (3)

Answer 2

Guanine nucleotide (GTP/GDP) binding proteins.
Composed of 3 subunits alpha, beta, gamma.
- Alpha: Binds GTP/GDP
- Beta/Gamma Allows G protein to bind to the receptor
Link drug-receptor reaction TO cellular response.

Question 3

G protein steps when drug binds (7)

Answer 3

1) No drug bound - GDP on a subunit
2) Drug binds
3) Change in receptor conformation
4) GTP binds to Ga subunit;
5) Ga dissociates from the receptor
6) Intrinsic Ga subunit GTPase activity - GTP dephosphorylates to GDP
7) G protein subunits (a,b,g) reassociate and bond with unbound receptor.

Question 4

G protein a subunits (5)

Answer 4

Determine what is activated inside the cell.
Different types, Gas, Gai, Gaq/11.
Diff a subunits interact with specific targets.
Intracellular messengers, cAMP, DAG, IP3.
Two main targets AC (adenyl cyclase) and phospholipase C (PLC).

Question 5

Gas and Gai - mediated adenylate cyclase pathways (6)

Answer 5

Change in biological response.
Often have opposing actions.
e.g. Gs increase heart rate. Gi inhibits heart rate.

Gi inhibits AC –> decreased cAMP –> inhibit PKA
Gs stimulates AC –> increased cAMP –> stimulate PKA –> Ion channels/ Enzymes/Transport proteins

Question 6

Gaq/11 - mediated phospholipase C pathway (7)

Answer 6

Increase in cytosolic [Ca2+].
Biological response.
e.g. Contraction of smooth muscle in eye, GI tract, blood vessel, airways.

IP3 binds to sarcoplasmic reticulum and opens up the pore allowing Ca2+ to leave the pore.
PLC –> PIP2 –> DAG + IP3
DAG –> PKC –> Ion channels
IP3–> Ca2+ –> Contractile protein

Question 7

Acetylcholine (5)

Answer 7

Receptors mediate responses of transmitters.
Diff speed of receptors generated by diff receptors.
Fast responses mediated by ion channel.
Slow response - biochemical cascade - lasts longer.
mAChRs - form GPCRs in cell membranes of neurones and other cells.