Abstract
Iron importer divalent metal transporter 1 (DMT1) plays a crucial role in the nigal iron accumulation in Parkinson’s disease (PD). Membrane hyperpolarization is one of the factors that could affect its iron transport function. Besides iron, selective activation of the ATP-sensitive potassium (KATP) channels also contributes to the vulnerability of dopaminergic neurons in PD. Interestingly, activation of KATP channels could induce membrane hyperpolarization. Therefore, it is of vital importance to study the effects of activation of KATP channels on DMT1-mediated iron uptake function. In the present study, activation of KATP channels by diazoxide resulted in the hyperpolarization of the membrane potential and increased DMT1-mediated iron uptake in SK-N-SH cells. This led to an increase in intracellular iron levels and a subsequent decrease in the mitochondrial membrane potential and an increase in ROS production. Delayed inactivation of the Fe2+-evoked currents by diazoxide was recorded by patch clamp in HEK293 cells, which demonstrated that diazoxide could prolonged DMT1-facilitated iron transport. While inhibition of KATP channels by glibenclamide could block ferrous iron influx and the subsequent cell damage. Overexpression of Kir6.2/SUR1 resulted in an increase in iron influx and intracellular iron levels, which was markedly increased after diazoxide treatment.
Highlights
Divalent metal transporter 1 (DMT1) is a ferrous iron importer and plays an important role in both iron uptake and iron translocation from the endosome[1]
Since there is a high density of KATP channels in the nigral dopaminergic neurons, which are selectively activated in PD15–17 and membrane potential hyperpolarization might enhance iron transport function of divalent metal transporter 1 (DMT1), it is of vital importance to study the effects of activation of KATP channels on DMT1’s iron transport function
To investigate the relationship between activation of KATP channels and DMT1-mediated iron transport function, using the quenching of calcein fluorescence indicated iron influx, we first observed the direct effect of activation of KATP channels on the iron transport function mediated by DMT1 in SK-N-SH cells
Summary
Divalent metal transporter 1 (DMT1) is a ferrous iron importer and plays an important role in both iron uptake and iron translocation from the endosome[1]. Besides iron insult to nigral dopaminergic neurons in PD, selective activation of the ATP-sensitive potassium (KATP) channels contributes to the differential vulnerability of dopaminergic neurons[15,16] Activation of these channels could induce membrane hyperpolarization due to ATP depletion and increased oxidative stress (ROS) in dopaminergic neurons. Since there is a high density of KATP channels in the nigral dopaminergic neurons, which are selectively activated in PD15–17 and membrane potential hyperpolarization might enhance iron transport function of DMT1, it is of vital importance to study the effects of activation of KATP channels on DMT1’s iron transport function. In the midbrain dopaminergic neurons, the KATP channels are composed of a pore-forming inward-rectifying potassium channel subunit, known as Kir6.2, and a regulatory sulfonylurea receptor subunit, known as SUR118 These subunits are metabolic sensors that couple cellular energy metabolism to the membrane potential by regulating potassium efflux. The effects of overexpression of KATP channels on iron influx were investigated in SK-N-SH cells
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