binding domain. When an appropriate protein ligand binds to this
domain, the receptor undergoes a conformational change that is
transmitted to its cytosolic regions which activate a trimeric GTP
binding protein or G protein for short.
- As the name implies a trimeric G protein is composed of 3 protein
subunits called alpha, beta and gamma. Both the alpha and gamma
subunits have covalently attached lipid tails that help anchor the G
protein in the plasma membrane. In the absence of a signal, the alpha
subunit has a GDP bound and the G protein is inactive.
- In some cases, the inactive G protein is associated with the inactive
receptor while in other cases, it only binds after the receptor is
activated. In either case, an activated receptor induces a
conformational change in the alpha subunit causing the GDP to
- GTP which is abundant in the cyotosol can now readily bind in place
of the GDP. GTP binding causes a further conformational change in
the G protein activating both the alpha subunit and the beta gamma
complex. In some cases, as shown the activated alpha subunit
dissociates from the activated beta-gamma complex whereas in other
case, the two activated components stay together. In either case, both
of the activated components can now regulate the activity of target
proteins in the PM as shown here for a GTP bound alpha subunit.
- The activated target proteins then relay the signal to other components
in the signalling cascade. Eventually the alpha subunit hydrolyzes its
bound GTP to GDP which inactivates the subunit. This step is often
accelerated by the binding of another protein called a regulator of G
protein signalling or RGS.
- The inactivated GDP bound alpha subunit now reforms an inactive G
protein with a beta-gamma complex turning off other downstream
- As long as the signalling receptor remains stimulated, it can continue
to activate G proteins. Upon prolonged stimulation however, the
receptors inactivate even if their activating ligands remain bound. In
this case, a receptor kinase phosphorylates the cytosolic portions of the
activator receptor. Once a receptor has been phosphorylated in this
way, it binds with high affinity to an arrestin protein which inactivates
the receptor by preventing its interaction with G proteins. Arrestins
also act as adaptor proteins and recruit the phosphorylated receptors to
clathrin coated pits from where the receptors are endocytosed and
afterwards, they can either be degraded in lysosomes or activate new
- So that goes over how G proteins coupled receptors transmit their
signals to the G proteins & then they go on & activate target proteins &
we looked at one of those target proteins & that is adenylyl cyclase.
! Phosphorylate specific substrate proteins
! Proteins phosphatases dephosphorylates target proteins
- An adenylyl cyclase will produce cyclic AMP from ATP in the cell.
- What happens downstream from that, how does cyclic AMP actually
transmit a signal to downstream signalling components in the cell?
- This is just an overview, here would be the activated G protein coupled
receptor bound to its ligand, this will activate the G alpha and the beta
gamma complex. These, especially the G alpha subunit when it is
activated can go and activate an adenylyl cyclase molecule. Then the
activated adenylyl cyclase will produce cyclic AMP from ATP.