Question

A vital feature that is true all signaling cascades is that they need to be shut down very quickly as soon as the extracellular signal is no longer present. Inspect the adrenaline signaling cascade in the figure above. Explain how each constituent of this signaling pathway is reverted to its inactive state as soon as adrenaline is no longer bound to its receptor.

Answer 1

It is true that all signalling cascades need to be shut down very quickly as soon as the extracellular signal is no longer present. Otherwise, function induced by continous stimulation of signalling cascade results in over function which is often deleterious.

Adrenaline (also called as epinephrine) is a hormone produced by body and bind to its receptor, adrenergic receptors or adrenoceptors.

These receptors belong to class of receptors called G protein-coupled receptor (GPCRs).

G protein-coupled receptor (GPCRs) are linked to trimeric G-proteins.

All G-proteins have 3 subunits - α, β and γ (heterotrimeric complex)

Binding of ligand Adrenaline to adrenergic receptors (GPCR) lead to conformational changes in receptor and activation of receptor and lead to dissociation of GDP and binding of GTP, from Gα subunit.

And, also dissociation of Gα-GTP from Gβγ.

Gα-GTP and Gβγ can interact with effector protein leading to changes in their activity.

When Adrenaline is no longer bound to its receptor, it cannot induce conformational changes in receptor and cannot activate G-protein complex. Without signal, heterotrimeric G-protein complex is in inactive GDP bound form.

Switch 'off' and 'on' mechanism for this signalling pathway

G-protein are GTPase switch proteins.

G-protein are turned on when bound to GTP and turned off when GDP is bound.

Gα subunit has intrinsic GTPase activity.

Gα subunit undergoes autoregulation due to its GTPase activity.

After short time of its activation it undergoes auto-inactivation due to its GTPase activity.

In many cases, protein called RGS (Regulator of G protein signalling) accelerates GTP hydrolysis by the Gα subunit.

RGS protein act as a Gα subunit specific GTPase activating proteins (GAPs)

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