Receptor Signalling

Question 1

4 types of Receptor Structure

Answer 1

Ligand-gated ion channel (4/5 TMDs)
- agonist bind = opens pore

G-Protein Coupled Receptor (7 TMD)
- extracellular N (binds to ligand)
- intracellular C (bind to G proteins)

Kinase-linked Receptor (1TMD)
- extracellular N (binds to ligand)
- intracellular C (catalytic domain)

Nuclear Receptor (0 TMD)
- effects in nucleus – found in cytosol or nucleus

Question 2

Nuclear Receptor Subtypes

Answer 2

I = Steroid Receptors (bind to steroid hormone in cytoplasm, dimerize, translocate to nucleus)

II = RXR Heterodimers (thyroid hormone translocate to nucleus, dimerize to RXR)

III - similar to type 1

Question 3

Structure of Nuclear Receptors

Answer 3

Transactivation (AF1) – bind site for regulatory proteins
DNA binding (DBD)
Ligand Binding (LBD)

Steroid Receptors – bind to palindromic DNA
RXR Heterodimers – bind to direct repeats DNA

Question 4

Receptor Tyrosine Kinases

Answer 4

agonist binds to RTK = 2 receptor to dimerize
cytosolic domains contact –> phosphorylate each other

Question 5

Ras/Raf/MAP kinase Pathway

Answer 5

growth factor binds to RTK = dimerize
tyrosine auto-phosphorylation
Grb2 binds and phosphophorylated
activates Ras (GTP–>GDP)
kinase cascade and gene transcription

Question 6

Epidermal Growth Factor Binding

Answer 6

hetero-dimerization of RTKs = functional flexibility
- EGFR2 inactive as monomer
- EGFR2/EGFR3 active

Question 7

Cytokine JAK Pathway

Answer 7

cytokine binds to cytokine receptor = dimerize
Jak phosphorylation
Stat binds, phosphophorylates, dimerizes
gene transcription

Question 8

Natriuretic peptide receptor (topology and ligand)

Answer 8

NPR-C binds to ANP, BNP, CNP (no intracellular domain)
NPR-A binds to ANP, BNP (kinase, dimerization, guanylyl cyclase domains)
NPR-B binds to CNP (kinase, dimerization, guanylyl cyclase domains)

Question 9

Ligand-Gated Ion Channels

Answer 9

convert chemical into electrical signals
- ligand bind = open/close channel = change in ion permeability

Question 10

Ligand-Gated Ion Channel Structure

Answer 10

Cys-loop superfamily
- 4/5 subunits each with 4 TMD (extracellular C and N)
- 5HT3, nicotinic ACh, GABA, glycine

Glutamate
- 4 subunits with 3 TMD (extracellular N, intracellular C)
- re-entrant ‘p-loop’ (M2)

PX2
- 3 subunits with 2 TMD (intracellular C and N)
- large extracellular loop

Question 11

Ligand-Gated Ion Channel Function and Selectivity

Answer 11

GABA/Glycine = anion + decrease excitability
Other = cation + excitatory

Concerted Channel Opening
- all binding domains occupied for channel to open
Subunit-Specific Channel Opening
- channels begins opening as agonist binds to domains