SEQUENCE OF APPEARANCE OF THE METABOLIC DERANGEMENTS IN RAT-BRAIN SYNAPTOSOMES DURING PHOSPHATE-DEPLETION

Chronic phosphate depletion (PD) causes a rise in basal level of cytos olic 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+ AT Pase. The chronology of the events that lead to these derangements is not elucidated. The present study examined this issue by evaluating th e 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 in itial derangement is a rise in the Vmax of Ca2+ ATPase during the firs t 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 t he 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 t he notion that PD is associated with an initial increase in calcium in flux into the synaptosomes. This is followed by a modest but significa nt rise in [Ca2+]i which in turn would inhibit mitochondrial oxidation and ATP generation leading to a decrease in ATP content. The latter c ompromises the activity of Ca2+ ATPase and Na+-K+ ATPase which are inv olved, directly or indirectly, in calcium extrusion out of the synapto somes. The increased entry of calcium combined with decreased calcium extrusion are followed by a further rise in basal levels of [Ca2+]i. T his sequence of events continues until a steady state is reached and i s characterized by reduced basal ATP content, reduced Vmax of Ca2+ ATP ase and Na+-K+ ATPase and elevated basal level of [Ca2+]i.