Regulation of Gap Junctional Communication by Astrocytic Mitochondrial K_ATP Channels following Neurotoxin Administration in in vitro and in vivo Models

Abstract

It is known that neuronal ATP-sensitive potassium (K_ATP) channels and astrocytic gap junctions (GJs) are involved in the mechanism underlying neurodisorders. The K_ATP channels exist also in glial cells, and the objective of this study was to determine whether the astrocytic K_ATP channels exert their effect on neurotoxin-induced neurodysfunction through regulating the astrocytic GJ function. The results showed that diazoxide, a selective mitochondrial K_ATP (mitoK_ATP) channel opener, enhanced the GJ coupling, but 5-hydroxydecanoate, a selective mitoK_ATP channel blocker that significantly inhibits GJ coupling in vitro did not. Activation of astrocytic mitoK_ATP channels alleviated kainic acid-induced dysfunction of GJ intercellular communication. Finally, activation of mitoK_ATP channels improved the astrocytic GJ coupling in the hippocampus after seizures due to the colabeling of GJ subunit connexin 43 and connexin 45 with glial marker and was increased substantially by the administration of diazoxide. Western blot demonstrated that the mitoK_ATP channels regulated the expression of connexin 43 (P2; active form) and connexin 45 in the epileptic hippocampus. These findings demonstrate that activation of astrocytic mitoK_ATP channels improves the GJ function in astrocytes, indicating that the effect of the astrocytic mitoK_ATP channels on neurotoxin-induced neurodysfunction might be, in part, through the regulation of the GJ-coupled spatial buffering in the hippocampus.

Opening of Astrocytic Mitochondrial ATP-Sensitive Potassium Channels Upregulates Electrical Coupling between Hippocampal Astrocytes in Rat Brain Slices

“…5B (control)]. We also measured transcellular diffusion of LY, and found that DIZ significantly increased the diffusion [29], [33]. Blockage of gap junctions with MFA completely inhibited this transcellular diffusion.…”

“…Astrocytes and fractions of membrane and mitochondria were prepared as described previously [33], [37] (see detail in Text S1). …”

“…We and other groups have demonstrated previously that activation of astrocytic mitoK ATP channels enhances gap junctional coupling and reverses neurotoxin-induced dysfunction of astrocytic coupling both in astrocytic cultures and brain tissues [33], [34]. However, blocking gap junction with meclofenamic acid (MFA) do not inhibit the electrical coupling between directly coupled astrocytes in hippocampal slices [13].…”

Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone

“…Beginning with our original observation in the neurovascular unit (43), a number of independent studies by other laboratories as well as our own have firmly established that mitochondrial-centered mechanisms are important initiators of the pre-and postconditioning response in neurons, astroglia, and cerebral endothelial cells (40,42,50,63,66,70,79,83,92,97,104,111,124,127,130). Mitochondrial-centered preconditioning also occurs in tissues such as myocardium (87), skeletal muscle (69), and peripheral endothelium (9,105).…”

Mitochondrial Mechanisms in Cerebral Vascular Control: Shared Signaling Pathways with Preconditioning

“…Additionally, BMS-191095 depolarizes mitochondria in cultured cortical neurons and enhances NO production by these cells . Thus, in addition to the endothelium, perivascular nerves, parenchymal neurons, and possibly astroglia as well [67,122], can provide mitochondrially-initiated vasoactive signals to VSM [82-84] for the final determination of integrated changes in cerebral vascular diameter (Figure 6). …”