3 - G Proteins & Enzyme Linked Receptors

Metabotropic Receptors

Receptors associated with G proteins and secondary messenger systems

GPCR

G-protein coupled receptor

single polypeptide

7 transmembrane domains (a-helices)

Ligand binds to either extracellular domain or within transmembrane domain (depending on type)

What are the effects of activating a G protein?

Activates an ion channel
Activates a second messenger (eg Ca)

Examples of G-protein activated enzymes

Adenylyl Cyclase —> activated by Beta 2 adrenoreceptor (second messenger enzyme)
Guanylyl Cyclase
Phospholipase C

What products are produced in reactions involving these G-protein activated enzymes?

- adenylyl cyclase

- guanylyl cyclase

- phospholipase C

ATP -> cAMP

GTP -> cGMP

PIP2 -> DAG/IP3

What is the effect of Protein Kinase A/Protein Kinase G on cAMP/cGMP?

Phosphorylates them to cause the response

What is the effect of Phosphodiesterase on cAMP/cGMP?

Dephosphorylates them to form AMP/GMP

How do GPCR's work?

Ligand binds to GPCR
GDP attached to alpha subunit swaps for GTP
GTP detaches the alpha unit from beta and gamma units
This activates the cell response

What are the two mechanisms of turning proteins on?

- GTP binding to G proteins —> exchange of GDP for GTP, switched off again by GTP hydrolysing back to GDP & protein itself
- Phosphorylation —> by kinase enzyme, switched off again by dephosphorylation by phosphase enzyme

How does Noradrenaline cause bronchodilation?

NA binds to beta 2 receptor
G protein activation
Activates & increases cAMP
Inhibits MLCK (myosin light chain kinase)
Causes bronchodilation

What are the affects of

- alpha adrenoreceptors?

- beta 1 adrenoreceptors?

- beta 2 adrenoreceptors?

increased BP and bronchoconstriction

increased HR

bronchodilation

Enzyme linked receptor

Have binding domain & kinase domain

Sit as monomers in membrane

Tyrosine kinase domain embedded in tail

Noradrenaline Structural Activity Relationship (SAR)

Increasing -OH groups on noradrenaline increases its potency

How do receptor tyrosine kinases work?

2 receptors stuck together
Causes 2 monomers to stick together and to phosphorylate tyrosine kinase
Causes cellular response