Sequence of Appearance of the Metabolic Derangements in Rat Brain Synaptosomes during Phosphate Depletion

Abstract

Chronic phosphate depletion (PD) causes a rise in basal level of cytosolic calcium ([Ca²⁺]i) in rat brain synaptosomes, a decrease in their ATP content and a reduction in Vmax of their Ca²⁺ ATPase and Na⁺-K⁺ ATPase. The chronology of the events that lead to these derangements is not elucidated. The present study examined this issue by evaluating the changes in rat in these parameters in brain synaptosomes during the evolution of PD over a period of 6 weeks. The results show that the initial derangement is a rise in the Vmax of Ca²⁺ ATPase during the first 2 weeks of PD. This is followed by a rise in [Ca²⁺]i, a fall in ATP content and decrease in the Vmax of Ca²⁺ ATPase and Na⁺-K⁺ ATPase by the end of the 3 week and most of these derangement worsened during the 4th to 6th weeks of PD. Taken together our data are consistent with the notion that PD is associated with an initial increase in calcium influx into the synaptosomes. This is followed by a modest but significant rise in [Ca²⁺]i which in turn would inhibit mitochondrial oxidation and ATP generation leading to a decrease in ATP content. The latter compromises the activity of Ca²⁺ ATPase and Na⁺-K⁺ ATPase which are involved, directly or indirectly, in calcium extrusion out of the synaptosomes. The increased entry of calcium combined with decreased calcium extrusion are followed by a further rise in basal levels of [Ca²⁺]i. This sequence of events continues until a steady state is reached and is characterized by reduced basal ATP content, reduced Vmax of Ca²⁺ ATPase and Na⁺-K⁺ ATPase and elevated basal level of [Ca²⁺]i.