Brain cells expend large amounts of energy sequestering calcium (Ca2+), while loss of Ca2+ compartmentalization leads to cell
damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P), a parent substrate to several metabolic
major pathways, including glycolysis. Recently, this laboratory discovered G6P significantly reduced Ca2+ accumulation in rat
brain endoplasmic reticulum (ER) microsomes. Since G6P diffusely reduces radiotracer 45Ca2+ accumulation in a pattern
similar to thapsigargin in fresh frozen rat brain sections, we hypothesized that G6P regulates Ca2+ accumulation by acting as an
endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA). Whole brain ER microsomes were pooled from
adult male Sprague-Dawley rats. Using radio-isotopic assays, 45Ca2+ accumulation was quantified following incubation with
increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA
activity, the simultaneous release of inorganic phosphate (Pi) coupled with Ca2+ accumulation was quantified. Addition of G6P
significantly and decreased Ca2+ accumulation in a dose-dependent fashion (1-10 mM). The reduction in Ca2+ accumulation was
not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate,
or other glucose metabolic pathway intermediates, had no effect on Ca2+ accumulation. Further, the release of Pi was markedly
decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca2+ uptake. Simultaneous
addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that
the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity.
Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca2+
dystasis caused by altered G6P regulation of SERCA activity.
CAPT William D. Watson, US Navy,graduated from Annapolis in 1984, completed his M.D. in 1997 and Ph.D.in 2000 at The Uniformed Services
University of the Health Sciences in Bethesda, MD, where he is currently the Vice Chair of the Department of Neurology after serving various
assignments, including Chair of Neurology at Bethesda Naval Hospital. He also is the currently appointed Neurology Specialty Leader, advising the
Navy Surgeon General on all matters relating to Navy Neurology. He has published 14 papers in reputed journals and serves as an editorial board
member of repute.
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