Abstract

The TREK family of mechano-sensitive potassium channels, comprising TREK-1, TREK-2 and TRAAK, are two pore domain (K2P) potassium channels and contribute to background potassium conductances in many cell types. Their activity can be regulated by a variety of physical and chemical stimuli.

There is increasing evidence to support a role of TREK channels in nociceptive processing. TREK channels contribute to the resting membrane potential of dorsal root ganglion neurons, whilst TREK knockout mice show increased sensitivity to painful stimuli. Pharmacological activation of postsynaptic TREK channels hyperpolarises the membrane of sensory neurons and depresses neuronal activity in the pain pathway thus countering excitation by noxious stimuli, offering hope of novel therapeutic advances in the treatment of pain.

Fenamate compounds, such as flufenamic acid (FFA) up-regulate the activity of TREK channels by binding directly to a negatively charged activator site. Mutation of specific residues of TREK-1 channels substantially reduces current, however this reduction can be reversed by FFA. Future experiments, such as gene editing, which utilise pharmacologically-reversible, loss of function mutations of TREK channels will help to clarify their importance in pathophysiological conditions such as pain.