Ischemic Postconditioning Reduces NMDA Receptor Currents Through the Opening of the Mitochondrial Permeability Transition Pore and KATP Channel in Mouse Neurons

Cell Mol Neurobiol. 2022 May;42(4):1079-1089. doi: 10.1007/s10571-020-00996-y. Epub 2020 Nov 7.

Abstract

Ischemic postconditioning (PostC) is known to reduce cerebral ischemia/reperfusion (I/R) injury; however, whether the opening of mitochondrial ATP-dependent potassium (mito-KATP) channels and mitochondrial permeability transition pore (mPTP) cause the depolarization of the mitochondrial membrane that remains unknown. We examined the involvement of the mito-KATP channel and the mPTP in the PostC mechanism. Ischemic PostC consisted of three cycles of 15 s reperfusion and 15 s re-ischemia, and was started 30 s after the 7.5 min ischemic load. We recorded N-methyl-D-aspartate receptors (NMDAR)-mediated currents and measured cytosolic Ca2+ concentrations, and mitochondrial membrane potentials in mouse hippocampal pyramidal neurons. Both ischemic PostC and the application of a mito-KATP channel opener, diazoxide, reduced NMDAR-mediated currents, and suppressed cytosolic Ca2+ elevations during the early reperfusion period. An mPTP blocker, cyclosporine A, abolished the reducing effect of PostC on NMDAR currents. Furthermore, both ischemic PostC and the application of diazoxide potentiated the depolarization of the mitochondrial membrane potential. These results indicate that ischemic PostC suppresses Ca2+ influx into the cytoplasm by reducing NMDAR-mediated currents through mPTP opening. The present study suggests that depolarization of the mitochondrial membrane potential by opening of the mito-KATP channel is essential to the mechanism of PostC in neuroprotection against anoxic injury.

Keywords: Ca2+; Ischemic postconditioning; Mitochondrial KATP channel; Mitochondrial permeability transition pore; NMDA receptor.

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Ischemic Postconditioning*
  • Mice
  • Mitochondrial Permeability Transition Pore
  • Neurons / metabolism
  • Receptors, N-Methyl-D-Aspartate

Substances

  • Mitochondrial Permeability Transition Pore
  • Receptors, N-Methyl-D-Aspartate
  • Adenosine Triphosphate

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