BMS2021 - W4: Cell Talk: Communication Networks Inside and Outside the Cell

GCPR (G-Protein-Coupled Receptors)

• have intracellular and extracellular component

• 7 transmembrane segments (protein threads itself in and out of cell membrane)

• Signalling molecule can activate multiple GPCRs

• All use G-proteins to relay a signal

G-proteins

GCPR interacts with a G protein (specifically Trimeric G-protein complex)

• have Α, β and γ subunits

• A subunit has a GDP/GTP binding site (activated through exchange of (GDP)

• specific GCPRs interact with specific G proteins

G protein activation

• Ligand binds to G -protein -linked receptor

• Receptor changes conformation and interacts with inactive, GDP -bound G protein

• Causes the G -protein to eject GDP and replace it with GTP → conformation change

• G protein dissociates from receptor → Alpha subunit (with bound GTP) dissociates from beta gamma subunits

• alpha subunit and beta gamma subunits can activate downstream effectors

• Switch is turned off when the G protein hydrolyses its own bound GTP to GDP

Second messengers

Effector enzymes are activated in response to activation of the receptor

• once activated, lead to synthesis or generation of a second messenger (small molecules or ion released into cell upon activation by effector enzymes)

Loss vs Gain of function mutations

Loss of Function mutations

• Leads to the inhibition of the signalling pathway and may present with symptoms comparable to a hormone deficiency.

Gain of Function mutations

• Mutations that lead to an overactive, constitutively active pathway and may present with symptoms similar to an excess of hormone or signalling molecule