Schematic representation of induction of and recovery from bupivacaine toxicity. (A) During toxicity, bupivacaine activates 5′-adenosine monophosphate–activated protein kinase (AMPK) with phosphorylation of threonine 172 and blocks protein kinase B (Akt), with the reduction of phosphorylation at serine 473 and some reduced phosphorylation of threonine 308. These two effects converse at tuberous sclerosis 2 (TSC2). AMPK activates TSC2 by phosphorylating it at serine 1387 with a decrease in inhibition of TSC2 by Akt. Kinases downstream of the mammalian target of rapamycin complex 1 (mTOR1) including p70 s6 kinase (p70s6k) and ribosomal protein s6 (s6) will be less activated. Feedback inhibition of insulin receptor substrate-1 (IRS1) by p70s6k is lost leading to sensitization of insulinergic signaling. (B) During recovery, IRS1 is hypersensitized so that at equivalent insulinergic stimulation there will be a hyperactivation of kinases downstream of IRS1 including Akt and glycogen synthase kinase-3β (GSK-3β). Both these proteins can control and assist with the recovery of cardiac contractility. AMPK remains phosphorylated and targets downstream of TSC2 and mTOR1 remain unactivated. ACC = acetyl-CoA carboxylase; PI3K = phosphoinositide-3-kinase.