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K ATP channel blockade protects midbrain dopamine neurons by repressing a glia‐to‐neuron signaling cascade that ultimately disrupts mitochondrial calcium homeostasis
Author(s) -
Toulorge Damien,
Guerreiro Serge,
Hirsch Etienne C.,
Michel Patrick P.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06785.x
Subject(s) - midbrain , dopamine , blockade , neuroscience , neuron , homeostasis , chemistry , microbiology and biotechnology , calcium , mitochondrion , biology , central nervous system , biochemistry , receptor , organic chemistry
J. Neurochem. (2010) 114 , 583–564. Abstract 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.