Negative regulation of receptor signaling

Question 1

Desensitisaton

Answer 1

Ability of a receptor-mediated response to plateau and them diminish despite sustained agonist exposure.
Protects cells from potentially toxic effects of superactivation.

Question 2

Receptor modification

Answer 2

Commonly invloves phosphorylation (GPCRs) or dephosphorylation (RTKs) and inactivation of receptor protein following agonist binding. Occurs in seconds/minutes

Question 3

Mechanisms responsible for desensitisation

Answer 3

Receptor modification
Receptor sequestration
Receptor downregulation
Induction of a receptor binding inhibitory protein

Question 4

Receptor sequestration

Answer 4

Internalisation of the receptor away from the cell surface into intracellular endosomal compartment.

Question 5

Receptor downregulation

Answer 5

Degradation of receptors (ie in Lysosomes) followoing their internalisation.

Question 6

Induction of a receptor binding inhibitory protein

Answer 6

Activation of signalling triggers gene expression and accumulation of inhibitory proteins that bind to and inactivate the receptor

Question 7

Types of receptor desensitisation

Answer 7

Homologous - receptor specific

Heterologous - not receptor specific

Question 8

Beta-adrenoceptor desensitisation

Answer 8

Cyclic AMP mediated desensitisation via PKA phosphorylation.
Homologous desensitisation via G-protein coupled receptor kinases (GRKs)
Arrestin binding (from GRK phosphorylation) triggers sequestration and degradation of the phosphorylated beta adrenoceptors.

Question 9

Desensitisation has two phases

Answer 9

Rapid phase due to receptor phosphorylation.
Slow phase due to receptor downregulation.

Recovery from rapid phase takes minutes (receptor dephosphorylation and recycling)
Recovery from slow phase takes hours (synthesisof New receptor proteins)

Question 10

Desensitisation of cytokine receptors

Answer 10

Cytokine binding to receptor dimers permits transphosphorylation on tyrosine and activation of receptor associated JAKs (Janus/just another kinase). Active JAKs phosphorylate specific tyrosine residues on receptors cytoplasmic domain. SH2 domains on STAT3 binds to Tyr-phosphorylated receptors and becomes phosphorylated by receptor bound activated JAKs. This forms dimers which translocate to the nucleas and initiates transcription of specific target genes. STATs also trigger the induction of SOCs (suppressors of cytokine signalling), they inhibit JAK activity and catalyse the polyubiquitylation of phosphorylated JAKs. Degredation of JAKs by proteosomes turns off signalling.