Inhibition of the synthesis of acetylcholine in rat brain slices by (-)-hydroxycitrate and citrate |
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Authors: | S Tucek V Dolezal A C Sullivan |
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Affiliation: | Institute of Physiology, Czechoslovak Academy of Sciences, Prague, Czechoslovakia;Hoffman-La Roche, Research Division, Nutley, New Jersey, U.S.A. |
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Abstract: | Abstract: Slices of rat caudate nucleus were incubated in a solution of 123 mM-NaCl, 5 mM-KCl, 1.2 mM-MgCl2, 1.2 mM-NaH2PO4, 25 mM-NaHCO3, 0.2 mM-choline chloride, 0.058 mM-paraoxon, 1 mM-EGTA, and oxidizable substrates. (−)-Hydroxycitrate, a specific inhibitor of ATP-citrate lyase (EC 4.1.3.8), used at a concentration of 2.5 mM, inhibited the synthesis of acetylcholine (ACh) from [1,5-14C]citrate by 82–86%, but that from [U-14C]glucose by only 33%, from [2-14C]pyruvate by 24% and from [1-14C-acetyl]carnitine by 8%; the production of 14CO2 from these substrates was not substantially changed. The synthesis of ACh from glucose and pyruvate was in hibited also by citrate; 2.5 mM- and 5 mM-citrate diminished it by 43% and 66%, respectively; the production of from [U-14C]glucose and from [1-14C]pyruvate was not affected. The mechanism of the inhibitory effect of citrate on the synthesis of ACh is not clear; the possibility is discussed that citrate alters the intracellular milieu in cholinergic neurons by chelating the intracellular Ca2+ and decreases the supply of mitochondrial acetyl-CoA to the cytosol. The results with (−)-hydroxycitrate indicate that the cleavage of citrate by ATP-citrate lyase is not responsible for the supply of more than about one-third of the acetyl-CoA which is used for the synthesis of ACh when glucose or pyruvate are the main oxidizable substrates. This proportion may be even smaller, since (−)-hydroxycitrate possibly affects the synthesis of ACh from glucose and pyruvate by a mechanism (unknown) similar to that of citrate, rather than by the inhibition of ATP-citrate lyase. |
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Keywords: | Acetylcholine synthesis Inhibition Citrate Hydroxy citrate Ca2+ chelation ATP citrate lyase |
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