Dynamic activation of K_ATP channels in rhythmically active neurons

Abstract

The respiratory centre within the brainstem is one of the most active neuronal networks that generates ongoing rhythmic activity. Stabilization of such vital activity requires efficient processes for activity‐correlated adjustment of neuronal excitability. Recent investigations have shown that a regulatory factor coupling electrical activity with cell metabolism comprises ATP‐dependent K+ channels (KATP channels), which continuously adjust the excitability of respiratory neurons during normoxia and increasingly during hypoxia. We used the single‐cell antisense RNA amplification‐polymerase chain reaction (PCR) technique to demonstrate that respiratory neurons co‐express the sulphonylurea receptor SUR1 with the Kir6.2 potassium channel protein. Single channel measurements on rhythmically active inspiratory neurons of the brainstem slice preparation of newborn mice revealed that KATP channels are periodically activated in synchrony with each respiratory cycle. The Na+‐K+‐ATPase was inhibited with ouabain to demonstrate that oscillations of the channel open probability disappear, although respiratory activity persists for a longer time. Such findings indicate that KATP channel open probability reflects activity‐dependent fluctuations in the ATP concentration within submembrane domains. We also examined the effects of extracellular [K+] and hypoxia. All changes in the respiratory rhythm (i.e. changes in cycle length and burst durations) affected the periodic fluctuations of KATP channel activity. The data indicate that KATP channels continuously modulate central respiratory neurons and contribute to periodic adjustment of neuronal excitability. Such dynamic adjustment of channel activity operates over a high range of metabolic demands, starting below physiological conditions and extending into pathological situations of energy depletion.

Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening KATPChannels

“…The principal consumer of ATP at the plasma membrane is the Na ϩ pump (Na ϩ ,K ϩ -ATPase), which is responsible for pumping out the Na ϩ that enters the neuron through cotransporters (such as those involved in neurotransmitter reuptake) and through the voltage-dependent Na ϩ channels that produce action potential firing. Activity leading to greater pumping has been demonstrated to produce K ATP activation in several preparations, including central neurons (Kabakov, 1998;Nguyen et al, 2000;Haller et al, 2001). This direct connection between the level of electrical activity and ATP consumption at the membrane makes K ATP channels ideal for an anticonvulsant role and predicts a correlation between the strength of the ketone body effect and the initial rate of firing, as we observed (Fig.…”

“…Best-known for their role in controlling insulin secretion from pancreatic ␤-cells (Ashcroft and Gribble, 1999), K ATP channels are also widely expressed in central neurons. Under typical recording conditions, they appear to be mostly shut, although they can be activated by metabolic insult (Yamada et al, 2001) or coincident with cellular activity (Haller et al, 2001). We suspected that K ATP channels play a role in the ketogenic diet or in the actions of ketone bodies, and we tested for this with channel inhibitors and with a knock-out mouse for the gene encoding Kir6.2, a principal channel-forming subunit of K ATP channels.…”

Stabilization of Bursting in Respiratory Pacemaker Neurons

“…After hyperpolarizing current injection, pacemaker neurons had intrinsic membrane properties that depolarized them into a V m in which they express pacemaker bursting. This may serve to enhance the stability of rhythmogenesis during variations in [K ϩ ] o , as occurs for bursting activity during normoxia (Haller et al, 2001;Somjen, 2002) and hypoxic conditions (Hansen, 1985;Müller and Somjen, 2000). Future studies ] o aCSF containing CNQX plus CPP, bicuculline, and strychnine) measured immediately after onset of current injection (x-axis) and immediately before the first burst ( y-axis).…”

“…Changes in [K ϩ ] o can have severe and even fatal consequences unless network or pacemaking mechanisms can compensate (Cohen et al, 1975;Johnson et al, 2001). Stabilization of this vital activity requires adjusting the excitability of neurons despite changes in [K ϩ ] o during sensory stimulation (Singer and Lux, 1975;Poolos et al, 1987), bursting during normoxia (Haller et al, 2001;Somjen, 2002), hypoxia (Hansen, 1985;Müller and Somjen, 2000), and epileptiform activity (Orkand, 1980;Jensen et al, 1994). The respiratory center within the brainstem must also face these challenges and indeed continues to be rhythmic over a range of [K ϩ ] o (Newstead et al, 1990;Peterson et al, 1992;Johnson et al, 2001).…”

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

“…Similarly, single channel recordings in brainstem inspiratory neurons show that bursts of single K ATP channel openings are in synchrony with the respiratory firing rhythm. The probability of open channels (P open ) is increased by approximately 60% after a strong burst of action potentials [103] . Blocking the Na + -K + ATPase reduces the increased P open of K ATP channels.…”