Glucose and hippocampal neuronal excitability: Role of ATP‐sensitive potassium channels

Abstract

Hyperglycemia-related neuronal excitability and epileptic seizures are not uncommon in clinical practice. However, their underlying mechanism remains elusive. ATP-sensitive K(+) (K(ATP)) channels are found in many excitable cells, including cardiac myocytes, pancreatic beta cells, and neurons. These channels provide a link between the electrical activity of cell membranes and cellular metabolism. We investigated the effects of higher extracellular glucose on hippocampal K(ATP) channel activities and neuronal excitability. The cell-attached patch-clamp configuration on cultured hippocampal cells and a novel multielectrode recording system on hippocampal slices were employed. In addition, a simulation modeling hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was analyzed to investigate the role of K(ATP) channels in the firing of simulated action potentials. We found that incremental extracellular glucose could attenuate the activities of hippocampal K(ATP) channels. The effect was concentration dependent and involved mainly in open probabilities, not single-channel conductance. Additionally, higher levels of extracellular glucose could enhance neuropropagation; this could be attenuated by diazoxide, a K(ATP) channel agonist. In simulations, high levels of intracellular ATP, used to mimic increased extracellular glucose or reduced conductance of K(ATP) channels, enhanced the firing of action potentials in model neurons. The stochastic increases in intracellular ATP levels also demonstrated an irregular and clustered neuronal firing pattern. This phenomenon of K(ATP) channel attenuation could be one of the underlying mechanisms of glucose-related neuronal hyperexcitability and propagation.

Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

“…Elevated extracellular glucose levels can evoke rapid changes in neuronal excitability through K ATP channels (23,24). K ATP channels are hetero-octameric proteins composed of 4 inner poreforming subunits (Kir6.1 or Kir6.2) and 4 sulfonylurea receptor (SUR) subunits.…”

Diabetic Hyperglycemia Aggravates Seizures and Status Epilepticus-induced Hippocampal Damage

“…One study suggested that the effect of glucose concentration on seizure susceptibility may be mediated via neuropeptide Y neurotransmission (Schwechter et al 2003). We previously showed that increases in extracellular glucose and intracellular ATP may attenuate ATP-sensitive potassium channels (K ATP ) by depolarizing neurons, which leads to a more excitable state (Huang et al 2007). As a coupling of metabolism to membrane electrical activity, K ATP is an important regulator of neuronal excitability and neuroprotection in metabolic stress, such as DH (Liss and Roeper 2001;Seino and Miki 2003).…”

The Potential Role of ATP-sensitive Potassium Channels in Treating Epileptic Disorders

“…From this point, it appears that the clinically relevant concentration would be similar to the concentration noted in our study. Although we have shown (Huang et al, 2007) that, in in vitro hippocampal neurons, K ATP agonists lead to membrane hyperpolarization and attenuate action-potential firing when extracellular glucose concentrations are high, there were no in vivo studies on whether K ATP agonists protect against seizure severity and consequent SE-induced hippocampal damage in rats with DH. In addition, the functional relationship between Kir 6.2 and SUR1 in DHrelated seizures remains unclear.…”

“…The stochastic increases in intracellular ATP levels also demonstrated an irregular and clustered neuronal firing pattern. Thus, this phenomenon of K ATP channel-attenuation could be one of the underlying mechanisms of glucose-related neuronal hyper-excitability and propagation (Huang et al, 2007) (Figure 1). Fig.…”

“…In rats with DH, diazoxide opened K ATP , which were frequently attenuated in a state of high extracellular glucose concentration (Huang et al, 2007). Diazoxide reduced glutamate release by opening presynaptic K ATP Kir 6.2/SUR1 channels (Bancila et al, 2004).…”