Fig. 6.

Development of vesicular ATP release blocker. a Both VNUT and VGLUTs require Cl⁻ for transport activity, which is inhibited by ketone bodies and glyoxylate through competition with Cl⁻ binding, resulting in the decreased vesicular release of ATP and glutamate [34, 35, 47, 96]. b Metabolic pathways affected by a ketogenic diet are illustrated. Pathways stimulated by the ketogenic diet are indicated in red and the metabolites affecting the Cl⁻ dependence on VGLUT2 are boxed. c Inhibitory potencies of glyoxylate and acetoacetate towards VNUT and VGLUT2 in the presence of 10 mM Cl⁻ were assayed and are shown as the concentration required for 50% inhibition (ID50). Neither acetoacetate nor glyoxylate inhibits VMAT, VGAT, or VAchT. N.I., no inhibition observed with 10 mmol/L. For details, see refs [47, 96]. In addition, very recently, both 2-phenylbutyrate and benzoylformate were found to be ineffective in blocking VGLUT2 at 5 mM [136]