Two‐pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26

Abstract

Chronic pain is a debilitating and increasingly common medical problem with few effective treatments. In addition to the direct and indirect economic burden of pain syndromes, the concomitant increase in prescriptions for narcotics has contributed to a sharp rise in deaths associated with drug misuse – the ‘opioid crisis’. Together, these issues highlight the unmet clinical and social need for a new generation of safe, efficacious analgesics. The detection and transmission of pain stimuli is largely mediated by somatosensory afferent fibres of the dorsal root ganglia. These nociceptive cells express an array of membrane proteins that have received significant attention as attractive targets for new pain medications. Among these, a growing body of evidence supports a role for the two‐pore domain potassium (K2P) family of K+ channels. Here, we provide a concise review of the K2P channels, their role in pain biology and their potential as targets for novel analgesic agents.

Where We Come From and Are We Aware of Where We Are Going To?

“…Ziconotide is one of them but has the disadvantage that it can only be administered intrathecally [79][80][81]. Some toxin-derived peptide drugs have been analysed, but the results are not consistent [82], while drugs that interact with the cellular membrane potassium channels are also being investigated [83]. Some recombinant proteins have been studied in the experimental setting, but they have not yet reached the clinical study phase [84].…”

Molecular determinants of chemical modulation of two‐pore domain potassium channels

“…However, the K2P channels are no longer considered merely “leakage” channels, but in fact have been demonstrated to play important regulatory roles in processes of high physiological and pathophysiological significance and are expressed in virtually all tissues (Renigunta et al., ). Past reviews have dealt with many aspects related to K2Ps such as their therapeutic potential (Es‐Salah‐Lamoureux, Steele, & Fedida, ; Mathie & Veale, ; Wiedmann et al., ), function (Niemeyer, Cid, Gonzalez, & Sepulveda, ; Renigunta et al., ; Schmidt et al., ), and pharmacology (Gada & Plant, ; Kim, ), revealing an ever‐expanding knowledge about their importance in living cells while presenting an increasing therapeutic interest as promising targets in cancer, pain, depression, and in diseases of the lung, heart, and kidney.…”

“…However, the K2P channels are no longer considered merely "leakage" channels, but in fact have been demonstrated to play important regulatory roles in processes of high physiological and pathophysiological significance and are expressed in virtually all tissues (Renigunta et al, 2015). Past reviews have dealt with many aspects related to K2Ps such as their therapeutic potential (Es-Salah-Lamoureux, Steele, & Fedida, 2010;Wiedmann et al, 2016), function (Niemeyer, Cid, Gonzalez, & Sepulveda, 2016;Renigunta et al, 2015;Schmidt et al, 2017), and pharmacology (Gada & Plant, 2019;Kim, 2005), revealing an ever-expanding knowledge about their importance in living cells while presenting an increasing 1.2 | K2Ps also possess unusual, yet important, biophysical properties Solving the first crystal structures of K2P channels revealed how their pore-lining helices (M2 and M4) can adopt two distinct conformations (Brohawn, Campbell, & MacKinnon, 2013;Brohawn, del Marmol, & MacKinnon, 2012;Miller & Long, 2012). These states were thus termed "up" and "down," as regarded by the relative placement and movement of the M2, M3, and M4 helices.…”

TRESK is a modality‐specific brake on nociceptor excitability

“…With its first member identified over 20 years ago (Lesage et al . 1996), this large family comprises 15 members with a high level of expression in sensory neurons (Gada & Plant, 2019). Indeed, sensory neurons of the dorsal root and trigeminal ganglia express different members of the K2P family, of which, TRESK, TREK‐1, TREK‐2 and TRAAK are highly expressed and present in pain‐sensing neurons (i.e.…”