Two-pore-domain potassium channels: regulators of many cellular functions

The structure and the gating mechanisms of two-pore-domain potassium channels (K2P channels) are becoming clearer [1–3], and we are now beginning to understand physiological functions of the 15 K2P channels present in the human genome. Originally, K2P channels have been regarded as passive leak channels that contribute to setting the resting potential, but in recent years, it has become clear that they can do much more than that. K2P channels are regulated in a very complex way, perhaps in a more complex way than most other potassium channels. They are sensitive to lipids, mechanical stretch, intraand extracellular pH, temperature, gases such as carbon monoxide and nitric oxide, and other physicochemical stimuli. Acute activation or inhibition of K2P channels plays a major role in the regulation of many cellular functions. In addition, the abundance of K2P channels at the cell surface can be regulated via G-protein-coupled receptors. Five of the K2P channels (TWIK-1, TWIK-2, THIK-2, TASK-5, KCNK7) have long been regarded as ‘silent’ channels because they could not be functionally expressed in heterologous expression systems and because no current attributable to these channels could be detected in native cells. However, two of these channels (TWIK-1 and THIK-2) have recently been characterised. It was found that their traffic to and from the surface membrane was regulated by constitutive endocytosis (TWIK-1) or by an intracellular retention signal (THIK-2). It is likely that they are functionally expressed under certain conditions, but their physiological function is still unclear. We expect that the role of the other ‘silent’ channels will be characterised in the near future. In the nervous system, K2P channels are critically involved in adjusting the resting membrane potential and shaping the firing properties of neurons. Based on this basal function and their multiple modulations, K2P channels represent important control elements for neuronal output. In thalamocortical relay neurons, TASK-1, TASK-3, and TREK-1 channels are stimulated or inhibited by a number of physicochemical stimuli including neurotransmitters of the ascending arousal system of the brainstem, thereby setting the activity modes of these neurons during wakefulness and sleep. Enhancement of potassium currents of the K2P family is a plausible mechanism for producing general anaesthesia, a condition with shows some similarities to natural deep sleep. TASK-1, TASK-3, and TREK-1 channels are opened by certain inhalational anaesthetics and are plausible candidates for mediating some of the central anaesthetic effects. TREK-1, TREK-2, and TRESK channels may be involved in the sensation of pain, and their upregulation may represent a possible strategy for the treatment of pain. TRESK channels are abundantly expressed in sensory neurons of the dorsal root ganglion; their unique properties, regulation, and pharmacology may be useful for developing selective activators of these channels. TASK channels are also involved in central and peripheral chemoreception and in the regulation of breathing, and some of these effects may be mediated by their sensitivity to extracellular pH. T. Budde :H.

Keywords:

• Potassium channel
• Resting potential
• Membrane potential
• Neuroscience
• Chemoreceptor
• Stimulus (physiology)
• Biochemistry
• Nervous system
• Dorsal root ganglion
• Chemistry
• Gating

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