Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

Abstract

M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 μM XE991 sensitized Aδ- but not C-fibers to noxious heat stimulation and induced spontaneous, ongoing activity at 32°C in many Aδ-fibers. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn (DH) neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Aδ-fiber peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Aδ-fiber responses and provide a rationale for the nocifensive behaviors that arise following intraplantar injection of the M-channel blocker XE991.

KCNQ Potassium Channels Modulate Sensitivity of Skin Down-hair (D-hair) Mechanoreceptors

“…M-current was found in bradykinin- (25,57) and capsaicin-(10) sensitive nociceptive neurons, in mas-related G-protein-coupled receptor member D (MrgD)-(58) and protease-activated receptor 2 (PAR-2)-(24) positive nociceptors, as well as in transient receptor potential cation channel subfamily M member 8 (TRPM8)-expressing cold nociceptors (29). Both KCNQ2 (26,28,29) and KCNQ5 (27) were postulated to be the predominant KCNQ subunit in these nociceptive neurons.…”

β-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a β-Subunit-Like Fashion

“…Because of its low voltage range for activation, I M generates a standing outward current below firing threshold that exerts a strong potential-clamping effect. By now, I M has been identified in numerous neurons of the peripheral and CNS (Jentsch, 2000;Brown and Passmore, 2009;Passmore et al, 2012). Depending on its subcellular location, a number of different electrophysiological functions have been attributed to I M (Yue and Yaari, 2006;Shah et al, 2011).…”

Kv7/M-type potassium channels in rat skin keratinocytes

“…Assuming that retigabine has a comparable effect on the response of keratinocyte TRPV3 channels to heat as that to carvacrol observed in the present study, retigabine would be expected enhance skin thermosensation. Thus, the fact that retigabine exerted the opposite (suppressant) effect on thermally-induced skin peripheral afferent discharges in situ [34] would seem to rule out the possibility that the latter effects were mediated indirectly via the keratinocytes. On the other hand, the effects of retigabine on keratinocyte responses might imply some limitation to the prospective utility of retigabine in suppressing pathological nociceptive activity [36].…”

“…In the course of a recent study on the location and function of M-type Kv7 K + channels in nociceptive sensory fibre terminals in the hairy skin of the rat paw [34], we noted that immunoreactivity for the Kv7.2 subunit was not restricted to the nerve fibres but could also be detected in the inner layer of the epidermis (J. Reilly, unpublished). In the present paper, we show that this results from its expression in skin keratinocytes and that these channels, which are normally associated with neurons, can play a functional role in modulating the stimulated release of ATP from the keratinocytes.…”