KATP channel blockade protects midbrain dopamine neurons by repressing a glia-to-neuron signaling cascade that ultimately disrupts mitochondrial calcium homeostasis.
While K(ATP) channels serve primarily as metabolic gatekeepers in excitable cells, they might also participate in other important cellular functions. Here, we demonstrate that K(ATP) channel blockade with the sulfonylurea derivative glibenclamide provided robust protection to dopamine neurons undergoing spontaneous and selective degeneration in midbrain cultures. Unexpectedly, glibenclamide operated not by a direct effect on dopamine neurons but instead by halting the proliferation of a population of immature glial cells lacking astrocytic and microglial markers. The antimitotic effect of glibenclamide appeared essential to unmask a prosurvival phosphoinositide 3-kinase (PI3K)/Akt-dependent signaling pathway that controlled shuttling of calcium from endoplasmic reticulum to mitochondria in dopamine neurons. Preventing integrin-ligand interactions with a decoy ligand, the Arg-Gly-Asp-Ser sequence peptide, reproduced survival promotion by glibenclamide via a mechanism that also required PI3K/Akt-dependent regulation of mitochondrial calcium. Noticeably, Arg-Gly-Asp-Ser did not cause a reduction in glial cell numbers indicating that it prevented the death process downstream of the level at which glibenclamide intervenes. Based on these results, we propose that K(ATP) channel blockade protected dopamine neurons by inhibiting a glia-to-neuron signaling pathway that propagates through integrin/ligand interactions and ultimately disrupts PI3K/Akt-dependent signaling and mitochondrial calcium homeostasis.
Toulorge
Damien
D
Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Unité Mixte de Recherche-S975, Paris, France.
Guerreiro
Serge
S
Hirsch
Etienne C
EC
Michel
Patrick P
PP
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology*; D006706:Homeostasis; D016023:Integrins / Q000502:physiology; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D016023:Integrins; D054086:KATP Channels; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D005905:Glyburide; D002118:Calcium; D004298:Dopamine