1-Methyl-4-Phenyl-l,2,3,6-Tetrahydropyridine and 1-Methyl-4-Phenylpyridinium Ions have Opposite Effects on Membrane Currents of Cultured Dorsal Root Ganglia Neurons

Abstract

The effects of the neurotoxin producing parkinsonism, 1-methyl-4-pheny 1-1,2,3,6-tetrahydropyridine (MPTP) and its biologically active metabolite, 1-methyl-4-phenyl-pyridinium ion (MPP⁺) on neuronal membrane currents were investigated to probe the hypothesis that membrane currents are affected as an initial effect of the neurotoxin. Membrane currents elicited by voltage ramps as well as voltage activated K ⁺-currents were studied in the whole cell patch clamp configuration using cultured dorsal root ganglia neurons of rats. While MPTP application in the bath caused no change or a slight increase in the total membrane current, MPP⁺ (1µM) resulted in a significant attenuation (up to 55%) of the currents. The K ⁺-currents elicited by voltage jumps from -80 to 0 mV were inhibited (>80%) by MPP⁺ (1µM), whereas MPTP (up to 5 µM) caused no effect on the voltage-activated K ⁺-currents. These findings support the hypothesis that MPP⁺ is the active neurotoxin that causes neurodegeneration and that the primary effects could be the blockade of one or more types of channels in the neurons. This is the first report that shows opposing effects of the parent molecule, MPTP and its biologically active metabolite, MPP⁺ on the electrical properties of the neurons. These first hand observations have far reaching implications, in that it clearly demonstrates for the first time that MPP⁺ affects the membrane conductance and this may be the key event that causes initiation of a cascade of events leading to neuronal damage.