Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose

One of the body's basic survival mechanisms is the neural machinery that triggers the hungry brain to the alertness needed for seeking food.

That same machinery swings the other way after a hearty meal, as exemplified by the long and honored custom of the siesta. However, scientists have understood little about how the basic energy molecule, glucose, regulates such wakefulness and other energy-related behaviors.

Now, in an article in Neuron, Denis Burdakov of the University of Manchester and his colleagues have pinpointed how glucose inhibits neurons that are key to regulating wakefulness. In the process, they have discovered a role for a class of potassium ion channels whose role has remained largely unknown. Such ion channels are porelike proteins in the cell membrane that affect cellular responses by controlling the flow of potassium into the cell.

The researchers set out to discover how glucose inhibits a particular class of glucose-sensing neurons that produce tiny proteins called orexins, which are central regulators of states of consciousness.

Wrote Burdakov and colleagues, "These cells are critical for responding to the ever-changing body-energy state with finely orchestrated changes in arousal, food seeking, hormone release, and metabolic rate, to ensure that the brain always has adequate glucose."

Malfunction of orexin neurons can lead to narcolepsy and obesity, and researchers have also found evidence that orexin neurons play a role in learning, reward-seeking, and addiction, wrote the researchers.

"Considering these crucial roles of orexin neurons, their recently described inhibition by glucose is likely to have considerable implications for the regulation of states of consciousness and energy balance," wrote Burdakov and his colleagues. "However, as in other glucose-inhibited neurons, it is unknown how glucose suppresses the electrical activity of orexin cells." What's more, they wrote, "Because the sensitivity of orexin cell firing to the small changes in extracellular glucose that occur between normal meals has never been tested, the daily physiological relevance of their glucose sensing is also unknown."

In their experiments, the researchers engineered mice to produce a fluorescent protein only in orexin neurons. Thus, the researchers could isolate the neurons in brain slices from the mice and perform precise biochemical and electrophysiological studies to explore how glucose acted on those neurons. In particular, the researchers performed experiments in which they exposed the neurons to the subtle changes in glucose levels known to occur in daily cycles of hunger and eating.

Their experiments showed that glucose inhibits orexin neurons by acting on a class of potassium ion channels known as "tandem pore" channels, about which little was known.

"Together, these results identify an unexpected physiological role for the recently characterized [tandem pore potassium] channels and shed light on the long-elusive mechanism of glucose inhibition, thus providing new insights into cellular pathways regulating vigilance states and energy balance," wrote Burdakov and colleagues.

"These results provide evidence that the firing rate of orexin cells is sensitive to changes in glucose that correspond to fluctuations occurring normally during the day and also show that the same electrical mechanism is involved in sensing both subtle and extreme changes in glucose," they wrote.

What's more, they wrote, their finding that subtle changes in glucose levels affect firing of orexin "raises the possibility that, besides being important for adaptive responses to starvation, modulation of orexin cells by glucose has a much wider behavioral role, contributing to the continuous daily readjustments in the level of arousal and alertness."

The researchers concluded that their findings "provide important new insights into how the brain tunes arousal and metabolism according to body-energy levels."