Protective role of neuronal KATP channels in brain hypoxia

Abstract

SUMMARY During severe arterial hypoxia leading to brain anoxia, most mammalian neurons undergo a massive depolarisation terminating in cell death. However,some neurons of the adult brain and most immature nervous structures tolerate extended periods of hypoxia–anoxia. An understanding of the mechanisms underlying this tolerance to oxygen depletion is pivotal for developing strategies to protect the brain from consequences of hypoxic-ischemic insults. ATP-sensitive K+ (KATP) channels are good subjects for this study as they are activated by processes associated with energy deprivation and can counteract the terminal anoxic-ischemic neuronal depolarisation. This review summarises in vitro analyses on the role of KATP channels in hypoxia–anoxia in three distinct neuronal systems of rodents. In dorsal vagal neurons, blockade of KATPchannels with sulfonylureas abolishes the hypoxic-anoxic hyperpolarisation. However, this does not affect the extreme tolerance of these neurons to oxygen depletion as evidenced by a moderate and sustained increase of intracellular Ca2+ (Cai). By contrast, a sulfonylurea-induced block of KATP channels shortens the delay of occurrence of a major Cai rise in cerebellar Purkinje neurons. In neurons of the neonatal medullary respiratory network, KATP channel blockers reverse the anoxic hyperpolarisation associated with slowing of respiratory frequency. This may constitute an adaptive mechanism for energy preservation. These studies demonstrate that KATP channels are an ubiquituous feature of mammalian neurons and may, indeed, play a protective role in brain hypoxia.

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

“…Changes in metabolic state or intracellular Ca 2þ concentration after ischemia can modulate a variety of K þ channels, including K ATP channels, Ca 2þ -activated large conductance K þ channels, and delayed rectifier voltage-dependent K þ channels (7,80,106). Recent evidence has shown that sublethal ischemic injury is associated with a protein-phosphatase 2B (PP2B or calcineurin)-dependent dephosphorylation of existing Kv2.1 channels, which is accompanied by a dispersal of somatodendritic Kv2.1 clusters and hyperpolarizing shifts in voltage-dependency (80).…”

Calcium- and Metabolic State-Dependent Modulation of the Voltage-Dependent Kv2.1 Channel Regulates Neuronal Excitability in Response to Ischemia

“…However, different neurons have distinct immediate and long-term protective mechanisms "on demand" to suppress the hyperexcitability induced by brief hypoxia/ischemia. One immediate mechanism is the depression of neuronal excitability during hypoxia/ischemia-induced activation of neuronal K ATP channels (Ballanyi, 2004), especially in neurons in anoxia-tolerant brain regions such as substantia nigra pars reticulata (Yamada et al, 2001), dorsal vagal neurons, and cerebellar Purkinje cells (Ballanyi, 2004). However, many brain neurons (e.g., hippocampal pyramidal neurons) express lower levels of functional K ATP channels (Zawar and Neumcke, 2000;Griesemer et al, 2002), such that brief hypoxia and ischemia in hippocampal slices induces immediate seizure-like hyperactivity followed by a delayed and prolonged suppression of neuronal activity (Kawasaki et al, 1990;Yamamoto et al, 1997).…”

Killer Proteases and Little Strokes—How the Things that do not Kill You Make You Stronger

“…Conversely, the neuroprotective potential of K ATP channel activation by agents such as diazoxide has also been demonstrated in animal models of brain ischemia (Ballanyi, 2004). It has been hypothesized that alterations in cellular redox status and generation of reactive oxygen species (ROS) elicit preconditioning by contributing to the opening of K ATP channels within the mitochondria (Avshalumov and Rice, 2003).…”