Dynamic activation of KATP channels in rhythmically active neurons

Abstract

1 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 (K_ATP channels), which continuously adjust the excitability of respiratory neurons during normoxia and increasingly during hypoxia. 2 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. 3 Single channel measurements on rhythmically active inspiratory neurons of the brainstem slice preparation of newborn mice revealed that K_ATP channels are periodically activated in synchrony with each respiratory cycle. 4 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 K_ATP channel open probability reflects activity‐dependent fluctuations in the ATP concentration within submembrane domains. 5 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 K_ATP channel activity. 6 The data indicate that K_ATP 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.