Mapping the Functional Expression Profile of Kv7 Channels in Somatosensory Neurons of Different Sensory Modalities

Pain is a regular and unavoidable experience that dramatically impacts people’s quality of life. Current treatments are often inadequate, expensive or invasive, thus, despite advances, the clinical need is still left unmet and new therapeutic targets are needed. Kv7 (‘M’) potassium channels may represent such a target as these impose strong control over neuronal excitability. Functional M channels are present in peripheral somatosensory neurons but there is currently no consensus as to what the functionally dominant subunit is. Here we combine measures of gene and protein expression with functional patch clamp analysis and behavioural testing to extensively study Kv7 in the peripheral sensory system. We demonstrated that all but Kv7.1 are expressed in rat sensory neurons and that Kv7.2, Kv7.3 and Kv7.5 are abundantly expressed. Kv7.2 showed a bias to small-diameter neurons and Kv7.5 toward larger neurons with significant overlap between the various subunits in rats and mice. Effects of Kv7.2/Kv7.3 selective potentiator, ICA-27243, and Kcnq2 knockdown suggest Kv7.2 is the predominant subunit controlling M current in TRPV1 positive nociceptors. ICA-27243 also significantly attenuated acute and inflammatory pain with comparable efficacy to retigabine. Kcnq2 knockdown significantly reduced the M current and rheobase in TRPV1 positive neurons and significantly increased the excitability of these neurons. This translated to a reduction in thermal and mechanical pain thresholds and an increased pain response to acute painful stimuli when Kcnq2 was knocked down in vivo. There were changes in some parameters associated with neuronal excitability and pain behaviour with Kcnq5 knockdown. These findings identified Kv7.2 as the functionally dominant Kv7 subunit in nociceptors and for response to painful stimuli.