Effect of Cholinergic Signaling on Neuronal Cell Bioenergetics

Abstract

Alzheimer's disease (AD) patients have reduced brain acetylcholine and reversing this deficit yields clinical benefits. In this study we explored how increased cholinergic tone impacts cell bioenergetics, which are also perturbed in AD. We treated SHSY5Y neuroblastoma cells with carbachol, a cholinergic agonist, and tested for bioenergetic flux and bioenergetic infrastructure changes. Carbachol rapidly increased both oxidative phosphorylation and glycolysis fluxes. ATP levels rose slightly, as did cell energy demand, and AMPK phosphorylation occurred. At least some of these effects depended on muscarinic receptor activation, ER calcium release, and ER calcium re-uptake. Our data show that increasing cholinergic signaling enhances cell bioenergetics, and reveal mechanisms that mediate this effect. Phenomena we observed could potentially explain why cholinesterase inhibitor therapy increases AD brain glucose utilization and N-acetyl aspartate levels. The question of whether cholinesterase inhibitors have a disease modifying effect in AD has long been debated; our data suggest a theoretical mechanism through which such an effect could potentially arise.

Investigation of the role of non-selective calcium channel blocker (flunarizine) on cerebral ischemic–reperfusion associated cognitive dysfunction in aged mice

“…The intracellular calcium ion accumulation is a major contributor in neuronal damage and oxidative stress (Gulati et al, 2013;Lam et al, 2013). The intracellular calcium ion is also responsible to alter the AChE level in brain tissue (Lu et al, 2013). In the present study results revealed that, the administration of flunarizine attenuated I/R induced rise in tissue calcium and AChE level.…”

Bioenergetic medicine

“…AChEIs typically yield modest but noticeable benefits. While increased cholinergic signalling likely initiates the therapeutic response, secondary changes in glycolysis and respiratory fluxes may also play an important role (Lu et al ., ; Figure ). Activating cholinergic muscarinic receptors generates inositol triphosphate (IP3), which binds endoplasmic reticulum (ER) receptors and induces ER calcium release.…”

“…Mitochondria absorb some of this calcium, and the resulting acute depolarization increases mitochondrial oxygen consumption (Cardenas et al ., ). Ultimately, sarcoendoplasmic reticulum calcium ATPase (SERCA) pumps return the calcium to the ER, which consumes ATP and through this effect stimulates glycolysis (Lu et al ., ).…”

“…Cholinergic signalling simultaneously activates both anaerobic and aerobic fluxes, which shows it is possible to overcome the inverse relationship these fluxes typically demonstrate (Lu et al ., ). In this specific case, increased cytosolic ATP consumption either counteracts or overrides the temporally concomitant increase in mitochondrial ATP production.…”

“…In this specific case, increased cytosolic ATP consumption either counteracts or overrides the temporally concomitant increase in mitochondrial ATP production. Also, alterations in proteins that sense and respond to cell energy levels change (Lu et al ., ). In particular, AMPK phosphorylation, which associates with AMPK activation, increases.…”