Physiology and Pharmacology 6: Receptors

Question 1

4 main classes of receptor in mammalian cells? Which require secondary messengers?

Answer 1

Ligand gated ion channel - Yes
GPCRs (7 Transmembrane receptors) - Yes
Directly coupled receptors (RTKs) - Yes
Intracellular receptors - No

Question 2

Characteristics of cell signalling through intracellular receptors

• examples of ligands
• what do ligands act as

Answer 2

• Require hydrophobic ligands that can diffuse through membrane
• Often called nuclear receptors
• Function as activators or repressors of genes

Ligands e.g. Testosterone, cortisol, Vit D, Retinoic acid
- act as regulated transcription factors

Question 3

Structure organisation of nuclear receptors?

Answer 3

N-terminal
-> AF1 (activation factor 1 domain, binds transcription factors)
-> Zn,Zn (DBD) (DNA binding domain)
-> Ligand binding Domain
-> AF2
-> NLS (nuclear localisation signal)
C-Terminal

Question 4

3 Nuclear receptor super families

- examples

Answer 4

• Steroids e.g. oestrogen, androgen, testosterone
• Non-steroidal lipophillic hormones e.g.Vit D3, retinoic acid
• Orphans -> no or unknown ligand

Question 5

2 Methods of signalling in nuclear receptors

Answer 5

Steroid receptor method

RXR (retinoid X receptor) heterodimer method

Question 6

Describe steroid receptor pathway

- use example of glucocorticoid receptor(GR)

Answer 6

• In Inactive state, GR is bound to heat shock protein(HSP)
• Upon ligand binding (cortisol), receptor undergoes conformational change and releases HSP, GR now free in cytosol
• Due to loss of HSP, new binding faces revealed
• Dimerisation domain allows GR to dimerise with partner receptor
• Both DBD and NLS domains are exposed
• Nuclear localisation signal(NLS) directs transportation to nucleus
• DNA binding domain binds to regulatory DNA sequences together with co-factors

Question 7

Decribe RXR heterodimer activation pathway

Answer 7

• In inactive state, exists already in nucleus bound to target DNA and repressed by co-repressor complex
• Ligand binds to RXR partner receptor, causing conformational change and release of co-repressor complex
• this allows (some) limited gene transcription
• New active sites are now revealed, allowing binding of CO-activator complex
• this fully activates receptors and allows full gene-transcription

Question 8

What are secondary messengers?

- examples

Answer 8

Intracellular messengers activated by respective extracellular receptors as ligands cannot diffuse through membrane
- e.g. calcium ions, cAMP, cGMP, IP3