THE effects of the mitochondrial Na+/Ca2+ exchange blocker tetraphenylphosphonium (TPP+) and the permeability transition blocker cyclosporinA (CysA) on the ability of mitochondria to participate in the regulation of intracellular calcium were investigated on freshly isolated mice sensory DRG neurons. The free intracellular calcium level ([Ca2+]in) was measured using indo-1 based microfluorimetry. The characteristics of depolarization-induced [Ca2+]in transients were changed in the presence of 25 μM TPP+. The amplitude of [Ca2+]in transients became decreased and the restoration of resting [Ca2+]in level speeded up in the presence of TPP+. Application of 5 μM cyclosporinA induced substantial residual elevation of [Ca2+]in after termination of depolarization. We conclude that the mitochondrial Na+/Ca2+ exchanger mechanism plays an important role in the regulation of calcium signals during neuronal activity, prolonging them by releasing Ca2+ stored during transient peak. Activation of permeability transition pores does not participate in these processes.