Kent Academic Repository Full text document (pdf) Citation for published version Mathie, Alistair and Veale, Emma L (2007) Therapeutic potential of neuronal two-pore domain potassium-channel modulators. Review of: therapeutic modulators by UNSPECIFIED. Current opinion in investigational drugs (London, England : 2000), 8 (7). pp. 555-62. ISSN 1472-4472. DOI Link to record in KAR https://kar.kent.ac.uk/75925/ Document Version Publisher pdf Copyright & reuse Content in the Kent Academic Repository is made available for research purposes. Unless otherwise stated all content is protected by copyright and in the absence of an open licence (eg Creative Commons), permissions for further reuse of content should be sought from the publisher, author or other copyright holder. Versions of research The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record. Enquiries For any further enquiries regarding the licence status of this document, please contact: [email protected] If you believe this document infringes copyright then please contact the KAR admin team with the take-down information provided at http://kar.kent.ac.uk/contact.html 555 Therapeutic potential of neuronal two-pore domain potassium-channel modulators Alistair Mathie* & Emma L Veale Address compounds act on these channels to alter their activity. In The Universities of Kent and Greenwich at Medway some instances, the action of these compounds may underlie Medway School of Pharmacy Central Avenue or contribute to their therapeutic activity. The physiological Chatham Maritime consequences of such activity may lead to the generation of Kent ME4 4TB compounds that selectively inhibit K2P channels for a UK particular therapeutic advantage. K2P channels can also be Email: [email protected] regulated indirectly (ie, by G-protein-coupled receptor *To whom correspondence should be addressed pathways and kinases), and thus compounds which interact with these indirect pathways also have important Current Opinion in Investigational Drugs 2007 8(7):555-562 physiological actions mediated via K2P channels. However, © The Thomson Corporation ISSN 1472-4472 it is beyond the scope of this review to also consider these indirect regulatory pathways (see reference [10] for Two-pore domain potassium (K2P) channels are expressed in cells examples). This review focuses on compounds that directly throughout the body and give rise to leak potassium currents modulate K2P channel activity, assesses the physiological which control the excitability of these cells. Although not inhibited consequences of such actions and discusses whether these by classical potassium channel-blocking drugs, such as (or any related, more selective, second-generation) tetraethylammonium and 4-aminopyridine, K2P channels are compounds provide further support for the potential regulated by a diverse array of pharmacological mediators. There targeting of K2P channels in CNS diseases such as stroke, are six main families of K2P channels and among these certain members of the TREK family (ie, TREK-1 and TREK-2) are epilepsy and depression. activated by general anesthetic agents such as halothane, xenon and nitrous oxide. In addition, all members of the TREK family General blockers of K2P channels are activated by neuroprotective agents, such as riluzole, An interesting pharmacological feature of K2P channels is polyunsaturated fatty acids and lysophospholipids, suggesting that that they are highly insensitive to both of the classical these channels play an important role in neuroprotection. TREK drugs used to block voltage-gated potassium channels: channels are also inhibited by chlorpromazine, local anesthetics tetraethylammonium (TEA) ions and 4-aminopyridine and the antidepressant fluoxetine. Furthermore, all members of the (4-AP). However, K2P channels can be blocked by barium TASK family are inhibited by cannabinoids and local anesthetics, ions and, in some cases, by quinidine and quinine. and TASK-3 is selectively inhibited by ruthenium red. Thus, the diversity and physiological importance of K2P channels suggest Quinidine and quinine that the development of selective compounds to target these Quinidine, a stereoisomer of the naturally occurring product proteins has therapeutic potential for CNS disorders such as quinine, is used as a class I anti-arrythmic agent in the heart stroke, depression and epilepsy. and affects many ion channels, including sodium, calcium and potassium channels. While quinidine blocks the TASK-1 Keywords Antidepressant, cannabinoid, ciclosporin, and TASK-3 K2P channels modestly (approximately 30% at fluoxetine, general anesthetic, lysophospholipid, neuro- 100 μM) [11-13], its effects on TREK-1 channels are more protection, polyunsaturated fatty acid, ruthenium red, two- varied. An early study of TREK-1 channels expressed in pore domain potassium channel Xenopus oocytes showed that the channels were unaffected by either quinidine or quinine [14]. However, later research Introduction with COS cells (transformed monkey kidney fibroblasts) Two-pore domain potassium (K2P) channels give rise to leak suggested that quinidine could block TREK-1 channels [15]. potassium currents and are expressed throughout the CNS Similarly, both quinine and quinidine block TWIK-2 channels [1,2] and in most other organs in the body [3•,4•,5•]. They but only when recordings are made in physiological potassium contribute to the resting membrane potential of neurons and solutions – no blockade has been observed in symmetrical regulate their excitability. While K2P channels are generally potassium solutions [16]. These latter observations highlight open at all voltages, they also display some voltage the importance of understanding the pharmacology of K2P dependency [6]. There are 15 members of the human K2P channels; the effectiveness of certain compounds is dependent channel superfamily, which can be divided into six main upon the experimental approach, and certain compounds families based on their structural and functional properties: (presumably those that interact with the permeation pathway) TREK, TASK, TWIK, TALK, THIK and TRESK (Figure 1) are influenced by the concentration and the net direction of [3•,4•,7-9]. Furthermore, K2P channels are regulated movement of the permeating ion. Of the other K2P channels, by a diverse array of pharmacological agents, TRESK [17,18] and TRAAK [19] are inhibited by both physiological mediators and neurotransmitter-activated quinidine and quinine. However, the situation for TALK pathways [3•,5•,7]. channels is more complicated. While both TALK-1 and TALK-2 channels are inhibited by quinidine (1 mM), quinine Currently, there are no compounds specifically designed to strongly inhibited TALK-1 channels and activated TALK-2 inhibit K2P channels; however, a large number of existing channels [20,21]. 556 Current Opinion in Investigational Drugs 2007 Vol 8 No 7 Figure 1. Dendrogram of the K2P channel superfamily. TASK THIK TASK-3 THIK-2 TASK-1 (K2P9.1) (K2P12.1) (K2P3.1) THIK-1 (K2P13.1) TASK-5 (K2P15.1) TRESK (K2P18.1) TRESK KCNK-7 (K2P7.1) TASK-2 TWIK-1 (K2P5.1) TWIK (K2P1.1) TALK-2 TWIK-2 (K2P17.1) TALK (K2P6.1) TALK-1 (K2P16.1) TREK-2 TRAAK (K2P10.1) TREK-1 (K2P2.1) (K2P4.1) TREK The 15 members of the K2P channel superfamily are shown according to their six main groups. The K2P nomenclature as approved by the International Union of Basic and Clinical Pharmacology is shown in parentheses (see reference [4•] for further details). Note that the KCNK-7, THIK-2 and TASK-5 subtypes are functionally silent when expressed in isolation. It is generally useful for a compound to selectively act on region is important for their anesthetic activity [23••]. In either a particular K2P channel family or an individual addition, the reduced sensitivity to volatile anesthetics in family member. The most extensively researched families of TREK-1 knockout animals [27••] suggests that the action of K2P channels are the TREK and TASK families, and as such volatile anesthetics on TREK-1 channels is of considerable this review focuses on compounds in relation to these two physiological importance. families. However, where effects of compounds have also been observed in other K2P channel families these will also Interestingly, gaseous anesthetics appear to selectively target be mentioned. and enhance the activity of TREK-1 channels (and presumably the related TREK-2 channels) with little action The TREK family of K2P channels on other K2P channels [26,28••]. The effect of these agents The TREK family (TREK-1, TREK-2 and TRAAK) is the most on TREK-1 activity was completely abolished by a single widely studied of the K2P channels and appears to show the amino-acid point mutation (ie, E306A) in the C terminus of largest diversity of regulation by pharmacological agents TREK-1 [28••], again confirming the importance of this [22]. A number of compounds have been identified which region in transducing the effect of many regulatory either upregulate or downregulate TREK channel activity, compounds on TREK-1 [29•]. The activation of TREK-1 and among these several compounds have shown important channels by gaseous anesthetic agents may also contribute to therapeutic actions, for example, as general anesthetic and their neuroprotective effects (see below and reference [26]). neuroprotective agents. Trichloroethanol (TCE; a metabolic by-product