The role of ATP in sleep regulation

Abstract

One of the functions of sleep is to maintain energy balance in the brain. There are a variety of hypotheses related to how metabolic pathways interact with sleep/wake regulation. A major finding that demonstrates an interaction between sleep and metabolic homeostasis is the involvement of adenosine in sleep homeostasis. An accumulation of adenosine is supplied from ATP, which can act as an energy currency in the cell. Extracellularly, ATP can act as an activity-dependent signaling molecule, especially in regard to communication between neurons and glia, including astrocytes. Furthermore, the intracellular AMP/ATP ratio controls the activity of AMP-activated protein kinase, which is a potent energy regulator and is recently reported to play a role in the regulation of sleep homeostasis. Brain ATP may support multiple functions in the regulation of the sleep/wake cycle and sleep homeostasis.

Keywords: AMPK; ATP; adenosine; astrocyte; sleep.

Figure 1

Schematic of the intra- and extra-cellular ATP/adenosine signaling cascades. Intracellularly, adenosine is formed from AMP by cytosolic 5′-nucleotidase. Adenosine kinase and adenosine deaminase convert adenosine to AMP and inosine, respectively. Extracellularly, ATP, ADP, and AMP are converted to adenosine by ecto-5′-nucleotidases. Intracellular and extracellular adenosine levels are regulated by bi-directional equilibrative nucleoside transporters.

Figure 2

Schematic of gliotransmission via astrocytic processes. Glutamate released from presynaptic neurons binds to postsynaptic AMPA receptors (AMPAR) and also to metabotropic glutamate receptors on astrocytes. This stimulates an increase in intracellular Ca²⁺ concentration in astrocytes, which in turn release ATP. Accumulation of adenosine from ATP breakdown in the extracellular space acts via adenosine 1 receptors (A1Rs) to depress synaptic activity.

Figure 3

Proposed model of increased AMPK activity during prolonged wakefulness. Prolonged wakefulness such as sleep deprivation activates central AMPK via decreased AMP/ATP ratio or increased CaMkk2 expression. An activation of AMPK enhances energy-producing catabolic pathways and attenuates energy-consuming anabolic pathways.