Protective Role of ATP-Sensitive Potassium Channels in Hypoxia-Induced Generalized Seizure

Abstract

Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata (SNr), the area with the highest expression of K(ATP) channels in the brain, plays a pivotal role in the control of seizures. Mutant mice lacking the Kir6.2 subunit of K(ATP) channels [knockout (KO) mice] were susceptible to generalized seizures after brief hypoxia. In normal mice, SNr neuron activity was inactivated during hypoxia by the opening of the postsynaptic K(ATP) channels, whereas in KO mice, the activity of these neurons was enhanced. K(ATP) channels exert a depressant effect on SNr neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures.

Molecular Targets for Antiepileptic Drug Development

“…141 Because K ATP channels may be activated mainly under conditions of neuronal energy failure (they are inhibited by ATP), such as in anoxia, openers of K ATP channels are unlikely to have broad utility in epilepsy therapy, although they might in theory be useful for the treatment of anoxia-induced seizures. 142,143 K ATP channels are, however, present in peripheral tissues, including the heart and vasculature; to date, no K ATP opener has been found that does not have adverse cardiovascular effects due to actions on these peripheral channels.…”

Nucleotide-gated KATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

“…Considering CK equilibrium in the membrane vicinity (12) and the relationships between concentrations (Eq. 11) and fluxes (Eqs 2, 7 and 8), values of ΔATP, ΔADP, ΔCr and ΔCrP can be derived as Eq.…”

“…At equilibrium, defining total bulk concentration for Cr plus CrP [CrT] = 40 mM [44], and total bulk nucleotide pool [TNP], it follows from Eq. 9: (10) At steady-state, total adenine nucleotide flux and total Cr/CrP flux, imply, due to Eqs 2 and 8, that (11) Considering CK equilibrium in the membrane vicinity (12) and the relationships between concentrations (Eq. 11) and fluxes (Eqs 2, 7 and 8), values of ΔATP, ΔADP, ΔCr and ΔCrP can be derived as Eq.…”

“…Since Cr and CrP diffuse in the aqueous phase 1.5 times faster than nucleotides, D Cr = 1.5D = 2.25 × 10 -11 cm 2 /s. Further, the equilibrium constant of the CK reaction: At steady-state, total adenine nucleotide flux and total Cr/CrP flux, imply, due to Eqs 2 and 8, thatConsidering CK equilibrium in the membrane vicinity (12) and the relationships between concentrations (Eq. 11) and fluxes (Eqs 2, 7 and 8), values of ΔATP, ΔADP, ΔCr and ΔCrP can be derived as Eq.…”

“…ATP-sensitive K + (K ATP ) channels are membrane metabolic sensors that adjust membrane excitability depending on the cellular energetic status [10][11][12]. K ATP channels are expressed in metabolically active tissues, such as the heart, where the pore-forming Kir6.2 protein assembles with the regulatory sulfonylurea receptor SUR2A subunit to form functional channels ( Fig.…”