A Role for K2P Channels in the Operation of Somatosensory Nociceptors

Abstract

The ability to sense mechanical, thermal, and chemical stimuli is critical to normal physiology and the perception of pain. Contact with noxious stimuli triggers a complex series of events that initiate innate protective mechanisms designed to minimize or avoid injury. Extreme temperatures, mechanical stress, and chemical irritants are detected by specific ion channels and receptors clustered on the terminals of nociceptive sensory nerve fibers and transduced into electrical information. Propagation of these signals, from distant sites in the body to the spinal cord and the higher processing centers of the brain, is also orchestrated by distinct groups of ion channels. Since their identification in 1995, evidence has emerged to support roles for K2P channels at each step along this pathway, as receptors for physiological and noxious stimuli, and as determinants of nociceptor excitability and conductivity. In addition, the many subtypes of K2P channels expressed in somatosensory neurons are also implicated in mediating the effects of volatile, general anesthetics on the central and peripheral nervous systems. Here, I offer a critical review of the existing data supporting these attributes of K2P channel function and discuss how diverse regulatory mechanisms that control the activity of K2P channels act to govern the operation of nociceptors.

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

“…C fibres can be subdivided, based on the expression of neuropeptides such as substance P, binding to the plant lectin IB4, or expression of thermosensitive TRP channels [96]. Acute localised pain is primarily transmitted by Aδ fibres, whilst diffuse pain, including itch, is mediated by C fibres (see [80]). …”

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

“…TRESK channels are abundantly expressed in almost all primary afferent neurons in trigeminal ganglion (TG) and dorsal root ganglion (Bautista et al 2008;Dobler et al 2007;Lafreniere et al 2010;Sano et al 2003;Yoo et al 2009). Previous studies indicate that TRESK is one of the major background K ϩ channels in dorsal root ganglion neurons and controls neuronal excitability under both normal and chronic pain conditions (Dobler et al 2007; Kang and Kim 2006;Liu et al 2013;Marsh et al 2012;Plant 2012;Tulleuda et al 2011). A frameshift mutation in the human KCNK18 gene that leads to the truncation of TRESK protein has been linked to migraine with aura in a large pedigree (Lafreniere et al 2010).…”

The LQLP Calcineurin Docking Site Is a Major Determinant of the Calcium-dependent Activation of Human TRESK Background K+ Channel

“…K2P background potassium channels are responsible for maintaining the highly negative resting membrane potential in different excitable cell types (1)(2)(3)(4)(5). Their regulation by voltageindependent mechanisms is of importance, since K2P channels generally determine the responsiveness of the cell to different excitatory stimuli and can also efficiently counter massive depolarization.…”

“…Background (leak) potassium channels are responsible for the hyperpolarizing outward potassium flux in a great variety of native cell types (1)(2)(3)(4)(5). Members of the K2P channel family, characterized by four transmembrane segments and two poreloop forming domains (4TM/2P) in each subunit of the functional dimer, give rise to background K ϩ conductance.…”