Glycogen breakdown and synthesis plays a critical role in regulating glucose homeostasis. The current issue of Cell Metabolism contains a paper published by Michale Bouskila from Kei Sakamoto's laboratory in the MRC Protein Phosphorylation Unit, which establishes for the first time the key role that allosteric activation of glycogen synthase plays in controlling the accumulation of muscle glycogen. The significance of her study is further discussed in a commentary by Matthew Brady (University of Chicago) in the same issue.
When the blood glucose rises after a meal, insulin is released from the pancreas to signal the body to lower the level of glucose. Insulin achieves this by promoting glucose uptake into muscle and by switching on the action of several enzymes, including glycogen synthase, a key regulator of glycogen formation. It has been known for over 40 years that glycogen synthase is activated allosterically by glucose-6-phosphate (G6P) and by dephosphorylation through insulin-induced inactivation of glycogen synthase kinase-3. However, despite decades of intensive research, the importance of the allosteric regulation of glycogen synthase was unknown due to the lack of a genetic handle on this process. To address this problem Michale first identified a key amino acid residue required for the activation of glycogen synthase by G6P. She then generated a 'knock-in' mouse in which the normal form of glycogen synthase was replaced by the G6P-insensitive mutant, which was still capable of being activated normally by dephosphorylation. Strikingly, Michale found that the insulin-stimulated accumulation of muscle glycogen and the muscle glycogen content were both greatly reduced in the knock-in mice. Michale's work provides compelling evidence that the allosteric activation of glycogen synthase is a major mechanism by which insulin promotes muscle glycogen accumulation in vivo.
When the blood glucose rises after a meal, insulin is released from the pancreas to signal the body to lower the level of glucose. Insulin achieves this by promoting glucose uptake into muscle and by switching on the action of several enzymes, including glycogen synthase, a key regulator of glycogen formation. It has been known for over 40 years that glycogen synthase is activated allosterically by glucose-6-phosphate (G6P) and by dephosphorylation through insulin-induced inactivation of glycogen synthase kinase-3. However, despite decades of intensive research, the importance of the allosteric regulation of glycogen synthase was unknown due to the lack of a genetic handle on this process. To address this problem Michale first identified a key amino acid residue required for the activation of glycogen synthase by G6P. She then generated a 'knock-in' mouse in which the normal form of glycogen synthase was replaced by the G6P-insensitive mutant, which was still capable of being activated normally by dephosphorylation. Strikingly, Michale found that the insulin-stimulated accumulation of muscle glycogen and the muscle glycogen content were both greatly reduced in the knock-in mice. Michale's work provides compelling evidence that the allosteric activation of glycogen synthase is a major mechanism by which insulin promotes muscle glycogen accumulation in vivo.