The Glycogenolysis Cascade

Glucagon binds to specific receptors in the plasma membrane of liver cells, called 1-adrenergic receptors causing an allosteric change in the receptor.

On the cytoplasmic face of these receptors are heterotrimeric G-coupled proteins composed of the alpha, beta and gamma subunits. Upon glucagon binding, the alpha subunit releases the bound GDP in exchange for GTP.

The GTP-bound alpha subunit is released of its inhibitory beta/gamma subunits and binds to adenylate cyclase.

The binding of the GTP-bound alpha subunit to adenylate cyclase triggers the production of cyclic AMP (cAMP) from ATP. cAMP is a small molecule second messenger which acts on the cAMP dependent protein kinase, cAPK, also known as protein kinase A, PKA.

cAPK is an oligomeric protein consisting of two regulatory and two catalytic subunits. In the absence of cAMP, this tetrameric complex is inactive. When cAMP is present, the binding of two molecules of cAMP to each of the regulatory subunits leads to the dissociation of the tetrameric complex. The dissociated catalytic subunits are now enzymatically active and capable of phosphorylating serine or threonine residues of target proteins.

Glucagon signals a need for an increase in blood glucose level. Therefore, the activated cAPK has a dual function. By phosphorylating glycogen synthase, cAPK inhibits the synthesis of glycogen. cAPK also phosphorylates glycogen phosphorylase kinase, the penultimate enzyme in the pathway of glycogen degradation.

Glycogen phosphorylase kinase then phosphorylates glycogen phosphorylase converting it into the active form, glycogen phosphorylase a, gpa capable of degrading glycogen to glucose 1-phosphate.