Phospho-AMPKα1 (Ser496) Recombinant Rabbit mAb

Phospho-AMPKα1 (Ser496) is a key inhibitory phosphorylation site located within the C-terminal regulatory domain of the AMPKα1 catalytic subunit. In contrast to the activating phosphorylation at Thr172 in the activation loop, phosphorylation at Ser496 negatively regulates AMPK kinase activity by weakening the interaction between the α and β subunits, thereby sterically hindering the access of upstream kinases to Thr172. This site can be phosphorylated by multiple upstream kinases, including PKA activated by the glucagon-cAMP signaling pathway and AKT activated by the insulin signaling pathway. More importantly, upon activation by AMPK activators (such as AICAR), AMPK itself can directly phosphorylate the Ser496 site on the α1 subunit, establishing a self-inhibitory negative feedback loop to prevent excessive AMPK activation. This phosphorylation has significant physiological and pathological implications: by impairing AMPK-mediated mitochondrial fission (via the MFF-DRP1 signaling axis), it reduces mitochondrial oxidative function, representing a key mechanism underlying aging- and obesity-related mitochondrial dysfunction. Persistently enhanced Ser496 phosphorylation, by blocking AMPK-mediated glucose uptake and autophagy, promotes hyperglycemia in metabolic syndrome. Therefore, designing targeted peptides to block Ser496 phosphorylation has emerged as a promising AMPK-activating strategy, and has shown potential in animal models for improving mitochondrial dynamics and alleviating hyperglycemia.