Small-Molecule Modulators of Inward Rectifier K ⁺ Channels: Recent Advances and Future Possibilities

Abstract

Inward rectifier potassium (Kir) channels have been postulated as therapeutic targets for several common disorders including hypertension, cardiac arrhythmias and pain. With few exceptions, however, the small-molecule pharmacology of this family is limited to nonselective cardiovascular and neurologic drugs with off-target activity toward inward rectifiers. Consequently, the actual therapeutic potential and 'drugability' of most Kir channels has not yet been determined experimentally. The purpose of this review is to provide a comprehensive summary of publicly disclosed Kir channel small-molecule modulators and highlight recent targeted drug-discovery efforts toward Kir1.1 and Kir2.1. The review concludes with a brief speculation on how the field of Kir channel pharmacology will develop over the coming years and a discussion of the increasingly important role academic laboratories will play in this progress.Members of the inward rectifier family of potassium (Kir) channels regulate a myriad of physiological processes, including cardiac function, pain processing and opioid action, learning and memory, insulin secretion and epithelial solute transport [1,2]. Some inward rectifiers occupy unique physiological niches that raise intriguing questions about their potential as therapeutic targets. Unfortunately, however, the small-molecule pharmacology of inward rectifiers has remained essentially undeveloped since the first member was cloned nearly 20 years ago [3]. This dearth of pharmacological tools has hindered efforts to develop even a cursory understanding of the physiology of some Kir channels and represents a critical barrier to defining their therapeutic potential. The main goals of this review article are:• To provide a comprehensive summary of disclosed small-molecule modulators of Kir channels, highlighting the few examples where pharmacology has illuminated a deeper understanding of their physiology and 'druggability'; © 2010 Future Science Ltd † Author for correspondence: Tel.: +1 615 343 7385, Fax: +1 615 343 3916, jerod.s.denton@vanderbilt.edu. Financial & competing interests disclosureThe authors are supported by NIH grants 1R21NS5704111 (Jerod S Denton) and 1U54MH084659-01 (Brian A Chauder), an American Heart Association-Southeast Affiliate Beginning Grant-In-Aid (Jerod S Denton), a National Kidney Foundation Postdoctoral Fellowhip grant (Gautam Bhave) and the Vanderbilt Department of Anesthesiology BH Robbins Scholars Program (Daniel Lonergan).The authors have no other relevant affliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript• To review recent adva...

The GIRK2 subunit is involved in IS‐like seizures induced by GABAB receptor agonists

“…Thus, G protein-mediated inwardly rectifying potassium channels, also known as Kir channels, preferentially conduct K + ions inwardly under voltage-clamp conditions. 27 The GIRK2/Kir3.2 channel in brain is coupled to GABA B R pre-and postsynaptically, 10,13 and also is activated by GHB through the GABA B R. [28][29][30] Upon stimulating the GABA B R, the G-bɣ subunit detaches and moves to the neighboring Girk channel to activate it. 31,32 Thus, by administering GABA B agonists, we were able to indirectly test the activity of the Girk2 subunit.…”

Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel

“…Since Ho et al (1993) and Zhou et al (1994) cloned ROMK nearly 20 years ago, the small-molecule pharmacology of the Kir family has remained largely undeveloped and limited to barium, cesium, and a handful of nonselective drugs exhibiting weak off-target activity toward Kir channels (for review, see Bhave et al, 2010). The slow progress in the field has hindered efforts to understand the physiology, clinical relevance, and therapeutic potential of certain Kir channels.…”

Localization and role of inward rectifier K+ channels in Malpighian tubules of the yellow fever mosquito Aedes aegypti

“…The slow kinetics is not consistent with the rapid, physical obstruction of open channels from the extracellular face of the channel. More likely, the slow kinetics suggests interactions of VU625 with intracellular parts of the channel protein, similar to the interaction of VU590 with mammalian Kir1.1, which first needs to cross the plasma membrane before it can block the intracellular pore of the channel (Bhave et al, 2010;Lewis et al, 2009). Alternatively, the slow kinetics may indicate that VU625 causes 1) C-type inactivation by deforming the selectivity filter of the channel and therefore impeding the passage of K þ (Sepulveda et al, 2015), and/or 2) disruptions in Kir channel activity by interfering with the channel gating that is regulated by agents such as PIP 2 , G proteins, and intracellular pH (Sepulveda et al, 2015).…”

“…13) and pharmacology. VU590 was originally discovered in a highthroughput screen for modulators of mammalian Kir1.1 channels (Lewis et al, 2009), and has been shown to inhibit mammalian Kir1.1 and Kir 7.1 channels by blocking the intracellular pore near the selectivity filter of these channels (Bhave et al, 2010;Lewis et al, 2009). In spite of its marked structural differences from VU625, VU590 also inhibits AeKir1 channels expressed in HEK-293 cells and Xenopus oocytes, but not AeKir2B channels expressed in Xenopus oocytes .…”