KCNQ-Encoded Potassium Channels as Therapeutic Targets.

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Annu. Rev. Pharmacol. Toxicol. 2018.58. Downloaded from www.annualreviews.org Access provided by Michigan Technological University - J. R. VAN PELT LIBRARY on 10/16/17. For personal use only.

Annual Review of Pharmacology and Toxicology

KCNQ-Encoded Potassium Channels as Therapeutic Targets Vincenzo Barrese, Jennifer B. Stott, and Iain A. Greenwood Vascular Biology Research Centre, Molecular and Clinical Sciences Institute, St George’s, University of London, London, SW17 0RE, United Kingdom; email: [email protected], [email protected], [email protected]

Annu. Rev. Pharmacol. Toxicol. 2018. 58:26.1–26.24 The Annual Review of Pharmacology and Toxicology is online at pharmtox.annualreviews.org https://doi.org/10.1146/annurev-pharmtox010617-052912 c 2018 by Annual Reviews. Copyright All rights reserved

Keywords KCNQ genes, Kv 7 channel, epilepsy, retigabine, smooth muscle contraction, arrhythmia

Abstract Kv 7 channels are voltage-gated potassium channels encoded by KCNQ genes that have a considerable physiological impact in many cell types. This reliance upon Kv 7 channels for normal cellular function, as well as the existence of hereditary disorders caused by mutations to KCNQ genes, means that pharmacological targeting of these channels has broad appeal. Consequently, a plethora of chemical entities that modulate Kv 7 channel activity have been developed. Moreover, Kv 7 channels are influenced by many disparate intracellular mediators and trafficking processes, making upstream targeting an appealing prospect for therapeutic development. This review covers the main characteristics of these multifunctional and versatile channels with the aim of providing insight into the therapeutic value of targeting these channels.

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Review in Advance first posted on October 6, 2017. (Changes may still occur before final publication.)

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1. INTRODUCTION Potassium (K+ ) channels determine a host of physiological responses, including the frequency and duration of action potential discharge, muscle contraction, transmitter release, and hormonal secretion. Opening of K+ channels causes K+ efflux, and the consequent hyperpolarization of the cell stabilizes the membrane potential and dampens cell excitability. The human genome contains over 70 genes that encode for K+ channels, most of which exhibit splice variants and all of which undergo multimeric assembly, considerably increasing the potential number of functional K+ channel species. This review focuses on one group of voltage-gated K+ channels (Kv), the Kv 7 family, which, since their initial molecular discovery in 1996, have been revealed as major players in the functional activity of numerous cell types, especially neurons, cardiac myocytes, as well as epithelial and smooth muscle cells. Kv 7 channels underlie K+ conductances with distinctive biophysical properties (see Table 1), which repolarize cells, thus reducing excitability. Their physiological relevance is underlined by the fact that mutations in Kv 7 channel–encoding genes (named KCNQs) are associated with several hereditary disorders, especially cardiac long QT syndrome, atrial fibrillation, epilepsy, and deafness (see Sections 5 and 6). The extensive research into Kv 7 channels has resulted in many publications concerned with the understanding of structurefunction characteristics, channel assembly motifs, modulation by specific intracellular molecules, and the development of an armamentarium of channel modifiers No review can do this panoply of data justice, so this article provides an overview of overarching themes and features, with a focus on the physiological impact of Kv 7 channels in neurons, cardiac cells, and smooth muscles.

2. KCNQ GENES AND KV 7 CHANNELS The KCNQ gene family comprises five members (KCNQ1–5) located at chromosomal loci 11p15, 20q13, 8q24, 1p34, and 6q13, respectively. Each KCNQ gene expresses a Kv 7 protein (Kv 7.1– Kv 7.5, respectively) of 650–940 amino acids, which assemble into a tetrameric K+ channel. Kv 7.1 forms homotetramers (1, 2), whereas the other subunits undergo heteromeric assembly (3, 4). Kv 7.3 consistently forms heteromers with Kv 7.2 or Kv 7.5, augmenting protein abundance in the plasma membrane (5). Kv 7.4 is less able to heteromerize with Kv 7.3 or Kv 7.2 but assembles readily Table 1

Biophysical properties of heterologously expressed Kv 7 channelsa Rate of activation (ms)b Consensus

Rate of deactivation at

Single-channel

Open probability

+40 mV

−60 mV (ms)

conductance (pS)c

at 0 mVd

210

90

455

1–4

0.1

209

130

153

6

0.2

−40

149

60

95

8.5

0.8

Kv 7.4

−20

179

160

103

2

0.07

Kv 7.5

−40

162

150

125

2

0.1

V0.5 (mV)b

0 mV

Kv 7.1

−20

Kv 7.2

−30

Kv 7.3

Subunit

a

Biophysical properties such as voltage dependence or kinetics of activation are variable and dependent on the recording system (i.e., whether the gene is expressed in Xenopus oocytes or a mammalian cell such as HEK or Chinese hamster ovary cells). b Voltage dependence of activation and rate of activation are taken as an averaged value from different studies (75, 111, 170–175). V0.5 is the value at which half maximal activation is recorded. c Single-channel properties are general taken from direct measurement from cell-attached recordings. However, the conductance from Kv 7.1 was derived from noise analysis (35, 176). d Open probability is taken from cell-attached patch recordings by different groups (e.g., 15, 23, 170).

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Extracellular

S1

S2

S3

S4

S5

S6

Intracellular

HN

Helix A


Tetramerization CaM binding PIP2 binding

Helix B

p38 MAPK, CaMKIIa, CDK5 AKAP yotiao (Kv7.1) AKAP79/150, PKC, PKA

Helix C (coiled coil)

Syntaxin 1 (Kv7.2 only) Ankyrin G (Kv7.2 only) Nedd 4-2 (Kv7.1 only)

Helix D (coiled coil) COOH

Figure 1 Schematic representation of a Kv 7 subunit with the six transmembrane domains and the intracellular N and C termini. The long C-terminal domain is organized in four helices (A–D) and contains most of the binding sites for regulatory proteins as well as the regions responsible for channel tetramerization, indicated with different colors. PIP2 binding sites can be also found in transmembrane domain linker regions. See text and References 8, 9, and 13 for more details. Abbreviations: CaM, calmodulin; PIP2 , phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C.

with Kv 7.5 (6), especially in vascular smooth muscle. Each Kv 7 channel is gated by membrane depolarization with activation thresholds close to the resting membrane potential in most cells (see Table 1), unlike most members of the Kv superfamily. Similar to other Kv channels, Kv 7 proteins comprise six transmembrane domains, with the voltage-sensing domain (VSD) being located within the first four segments (S1–S4), whereas the last two segments (S5–S6) and linker comprise the pore-forming domain (PD); a short N terminus and a long C terminus, both intracellular, are also present (Figure 1) (7). The C terminus of Kv 7 channels is considerably longer than that of other Kv channels and is organized in four distinct helices (A–D) that contain crucial sites for protein tetramerization (1, 2) and interaction with several modulators, including kinases, scaffold proteins, and ubiquitin ligases (summarized in Figure 1 and reviewed in References 8–10). Such molecules regulate the biophysical properties of Kv 7 channels and/or their trafficking, folding, and heteromerization, often dynamically modulating the affinity and binding of each other (11). All Kv 7 channels have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP2 ) to be active (12, 13). PIP2 increases open probability by stabilizing the channel open configuration (14, 15). In addition, in Kv 7.1 PIP2 enhances coupling between the VSD and the pore, making the opening of the channel in response to changes in the membrane potential more efficient (16). Depletion of PIP2 by phospholipase C is a main mechanism for G protein–coupled receptor–induced downregulation of Kv 7 channel function (Figure 2) (17). All Kv 7 channels are also modulated by calmodulin (CaM), which binds constitutively to the C terminus to ensure proper Kv 7 channel folding and tetramerization and possibly to orientate channel subunit composition at distinct parts of the cell (18). Increases in intracellular calcium (Ca2+ ) drive a switch from an apo-CaM form that bridges helices A and B to a Ca2+ /CaM form bound to helix B only (19–21). This rearrangement brings about the Kv 7.2–4–5 suppression and Kv 7.1 activation seen in response to increased intracellular www.annualreviews.org • Therapeutic Targeting of KCNQ Channels


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a i.

Spike-frequency adaptation

Kv7

LEGEND

Kv7 Syn1A 2 3 5


2 3 5

ii.

Kv7 channels 4 K 7.4 v 5 K 7.5 v

1 Kv7.1 2 Kv7.2 3 Kv7.3

E1 KCNE1 E4 KCNE4

AnkG

AnkG

mAHP sAHP

2 3 5

Kv7

M receptor

2 3 5

NEURON

iii.

PIP2

Gq

Neurotransmitter release

DAG

PLC

IP3

b 1 E1

IKS

Kv7

β-AR 4 Gα

CARDIAC CELL

Kv7

Kv7

Kv7

NPR

1 E4

AC9 PKA

PKA

c Basal

P AKAP9

AKAP9 AC9

Gβγ

Gβγ

β-AR Gβγ

4 5

SMOOTH MUSCLE CELL

cGMP

cAMP

Figure 2 A summary of functional roles, Kv 7 subunit expression profiles, and regulation in neurons (a), cardiac myocytes (b), and smooth muscle myocytes (c). Kv 7 subunits are represented by different colored boxes. KCNE isoforms pertinent to the cell type are shown as green boxes. The Kv 7 subunits expressed in neurons, smooth muscle cells, and myocytes are shown. Inserts show representations of the functional impact of Kv 7 channels in the three cell types. In neurons, Kv 7.2/7.3 channels contribute to spike frequency adaption and regulation of transmitter release. Kv 7.5 contributes to slow afterhyperpolarization. In cardiac myocytes, the Kv 7.1/KCNE1 channel complex contributes to the late repolarization of the action potential (red ). For the smooth muscle, a representation of a phasic smooth muscle is shown highlighting that increased Kv 7 activity suppresses contraction, whereas blockade of Kv 7 channels increases contraction. Illustrations to the right represent examples of regulatory pathways that have been characterized in the given cell type. These are inhibition of Kv 7.2/7.3 by muscarinic receptor activation in neurons via PIP2 depletion; increase in Kv 7.1/KCNE1 channels following β-AR stimulation and phosphorylation by PKA in cardiac myocytes; and increase in activity of Kv 7.4/7.5 in smooth muscle by cAMP (e.g., β–AR) and cGMP (NPR)-linked receptors, which involves an obligatory role for Gβγ. Abbreviations: β-AR, β-adrenoceptor; 9DAG, diacylglycerol; AC9, adenylate cyclase isoform; AnkG, ankyrin G; Gβγ, G protein βγ subunits; IP3 , inositol triphosphate; mAHP, medium After hyperpolarization; NPR, natriuretic peptide receptor; PIP2 , phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PLC, phospholipase C; sAHP, slow after hyperpolarization; Syn1A, syntaxin 1A.

Ca2+ (22–24). As the binding sites for PIP2 and CaM are close and partially overlapping, it is not surprising that some of the effects of CaM on Kv 7 function seems to be due to modulation of PIP2 affinity (Kv 7.2) (13) or binding (Kv 7.1) (25). The complexity and interdependence of different modulators on Kv 7 regulation is further demonstrated by recent evidence showing that G protein βγ subunits (Gβγ) cooperate synergistically with PIP2 to increase Kv 7.4 currents (26). Inhibition of either arm precludes the effect of the other, whereas subthreshold concentrations of Gβγ enhance the effect of submaximal concentrations of PIP2 (26). The crucial role of the C terminus in Kv 7 26.4

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channels is highlighted by the fact that many disease-causing mutations are found within it (8, 27). Moreover, variations in the C terminus underlie many of the features that are unique to individual Kv 7s, such as the propensity to form homo- or heterotetramers (28). Therefore, the C terminus may represent an interesting target to selectively modulate individual Kv 7 channel subunits.


3. THE ROLE OF THE KCNE-ENCODED AUXILIARY SUBUNIT Single transmembrane proteins encoded by KCNE1–5 (29–31) have a marked effect on many properties of Kv 7 subunits, including rate of activation, degree of inactivation, abundance in the cell membrane, and pharmacological responsiveness (see Section 4, Table 2, and Reference 32). All Kv 7 subunits are modified to some extent by KCNE proteins; however, the best-studied associations are Kv 7.1 with KCNE1-encoded auxiliary subunits. Kv 7.1 associates with KCNE1 proteins at a ratio of 4:2, although more KCNEs might be accommodated (30, 31). The interaction with Table 2 Compounds acting on Kv 7 channels and in vivo evidence for their potential therapeutic use beyond arrhythmia and epilepsy Evidence in vivo for potential new Compound

Selectivity

therapeutic uses

Blockers Linopirdine

All (IC50 = ∼5 μM)

Cognition enhancer (see 177, 178) Increases vascular resistance and blood pressure (156)

XE991

All (∼10-fold more potent on Kv 7.1 channels compared to Kv 7.1/KCNE1) (179)

Cognition enhancer (180, 181)

Chromanol 293B

Kv 7.1 + KCNE1/E3 > Kv 7.1

Enhances glucose-stimulated insulin secretion (182)

HMR1556

Kv 7.1 + KCNE1 > Kv 7.1

Anti-arrhythmic

JNJ303

Kv 7.1 + KCNE1 > Kv 7.1 No effect on heteromers with other KCNEs (48)

Anti-arrhythmic

U1026

None

Enhancers RL-3

Kv 7.1 KCNE1 or KCNE3 coexpression abolishes stimulation (183, 184)

None

ML277

Kv 7.1

None

Mefenamic acid

Kv 7.1 + KCNE1

None

Retigabine (ezogabine)

Kv 7.2–7.5 Binding site is formed by a key tryptophan in the S5 domain [W36 in Kv 7.2, as well as leucines within the S5 domain, inner pore, and S6 domain (Leu243, Leu 275, Gly301, Leu299)] (61, 62) Enhancer but inhibits at positive potentials (57, 63, 163) Blocks Kv 7.1 at 100 μM Suppress neuronal Kv 2.1 currents (185) Modulator of extrasynaptic δ-containing GABAA receptors (186)

Antidepressant (142) Antihypertensive (187) Analgesic (188) Anxiolytic (141) Protects against peripheral salicylate ototoxicity (189) Antimanic (190) Anti-ischemic in brain (125)

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(Continued)

Compound

Selectivity

Evidence in vivo for potential new therapeutic uses


Enhancers Flupirtine

Kv 7.2–7.5

Anti-ischemic in brain (191) Antidepressant (142) Antihypertensive, including pulmonary hypertension (156, 192, 193) Reduces memory impairment (194) Efficacy in cocaine addiction (195)

Acrylamide S-1/S-2

Kv 7.4 > Kv 7.2, Kv 7.3, and Kv 7.5 Bimodal effect on Kv 7.2 channels. The stimulatory effect is lost upon mutation of W242. A methylated variant of S-2 was a pure stimulant of Kv 7.4 and inhibitor of Kv 7.2 (196, 197).

ML213

Kv 7.2 = Kv 7.4 Kv 7.3 and Kv 7.5

BMS-204352 (Maxipost)

None Antidepressant (142) Anxiolytic (141) Abolishes behavioral evidence of tinnitus (198) Protects against peripheral salicylate ototoxicity (189)

NH29

Kv 7.2 and Kv 7.2/7.3 > Kv 7.4 > Kv 7.3

ICA-27243

Kv 7.2/7.3 > Kv 7.4 and Kv 7.5

Analgesic (inflammatory pain) (188) Reduces L-DOPA–induced dyskinesia (199) Antimanic (190)

ICA-069673

Kv 7.2 > Kv 7.3; Kv 7.4 > Kv 7.5

None

Zinc pyrithione

Kv 7.1–7.5 (Kv 7.3?) No effect on heterologous Kv 7.1 + KCNE1/KCNE3 and native IKs (200) In Kv 7.2, the binding site is formed by two leucines (amino acids 249 and 275) and an alanine (position 306), located between a gating hinge glycine at 301 and the Pro-Ala-Gly bend in the S6 domain The hyperpolarizing shift of ∼25 mV is conserved when A306 is mutated, but there is no increase in conductance, whereas mutation of leucines shows the opposite

None

AaTXKβ (2–64)

Kv 7.2, 7.2/7.3, and 7.4 (201)

None

Phenylboronic acid

At 10 mM, activates Kv 7.1 either as a homomer or in complex with proteins expressed by KCNE1 and KCNE3 through a shift in voltage dependence and increased maximal conductance (202)

None

NS15370

Antipsychotic (203)

Meclofenac

Kv 7.2/7.3

Dysmenorrhea

Diclofenac

Kv 7.2–7.5 Enhances homomeric Kv 7.4 channels, blocks homomeric Kv 7.5 channels, and has intermediate effects on heteromeric Kv 7.4/7.5 channels (204)

Painkiller, anti-inflammatory

Abbreviations: IKs , slowly activating delayed rectifier current in cardiac cells; L-DOPA, levodopa. 26.6

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KCNE1 proteins slows the activation kinetics, shifts the voltage dependence of Kv 7.1 to positive voltages (33, 34), increases channel numbers in the membrane, and increases the single-channel conductance (35). Various amino acids within S1, S4, S6, and the C terminus of Kv 7.1 are crucial for KCNE1-mediated modification (31, 36–38). In contrast, coexpression of Kv 7.1 with KCNE2 or KCNE3 proteins results in constitutively active currents as the channel becomes locked in an open configuration (39, 40). Melman et al. (41) revealed that switching a single amino acid in the auxiliary protein (T58 in KCNE1, V72 in KCNE3) altered completely the effect on Kv 7.1. V72T-KCNE3 protein slowed activation of Kv 7.1 as much as wild-type KCNE1, and T58VKCNE1 produced a constitutively open channel. KCNE4 and KCNE5 suppress Kv 7.1 channel activity through a rightward shift in the voltage sensitivity (42). The effects of KCNE proteins on other Kv 7s are less well reported, although KCNE4 augmented Kv 7.4 channel presentation in the cell membrane and increased the rate of activation (43–45). Why is Kv 7.1 so susceptible to modulation by KCNE proteins? The consensus is that, due to the structural differences in the S4 and S6 segments, Kv 7.1 channels have a lower open probability with respect to other Kv 7 subunits (46, 47) and have a fenestrated tertiary structure amenable to protein interaction (48). KCNE1 binding not only increases Kv 7.1 open probability but also enhances its sensitivity to PIP2 (49). The complexity of Kv 7:KCNE protein interactions is only just being unearthed (50) and may yield novel therapeutic targets.

4. PHARMACOLOGY Fueled primarily by the pharmaceutical industry’s hunt for new epileptic agents and the identification of alternate therapeutic targets, the number of Kv 7 modulators has exploded over the past decade (51, 52). Several structurally dissimilar agents have been developed that target Kv 7 channels (summarized in Table 2), and within this list, three broad themes have become apparent. First, Kv 7.1 is pharmacologically distinct from the other family members. All Kv 7 channels are blocked by linopirdine and XE991 with similar IC50 values (∼5 and ∼0.8 μM, respectively), but only Kv 7.1 has subunit-specific inhibitors [chromanol 293B, HMR1556, L-7, JNJ282, and JNJ303 (53)] and activators (ML277 and RL-3). The effectiveness of Kv 7.1 modulators is profoundly affected by the presence of KCNE1 and KCNE3 subunits (54–56). The second theme is that Kv 7.2–7.5 channels are enhanced selectively by drugs acting at three distinct binding sites. Retigabine (ezogabine, Potiga) is a novel antiepileptic that increases open probability, causes a ∼15-mV leftward shift in the voltage-dependence of activation, and decreases the rate of deactivation of Kv 7.2–7.5 channels (57–59) through an interaction with a binding site in the pore region localized around a key tryptophan (236 in Kv 7.2) (60–62). This amino acid is lacking in Kv 7.1, resulting in the channel being resistant to stimulation by this compound (57, 63). Many structurally diverse compounds (acrylamides S1 and S2, BMS-204352, ML213, and NS15370) also bind to the retigabine site. In contrast, a second group of activators bind to the VSD, either at the S4 segment (diclofenac, meclofenac, and NH29) or at the S2–S3 linker (ICA-27243 and ICA-069673). Zinc pyrithione enhances all Kv 7 channels through an interaction in the pore region that is distinct from the tryptophan-based retigabine pharmacophore (64). Additional compounds increase Kv 7 channel activity by redox modification (N-ethylmaleimide and hydrogen peroxide). The third overarching theme is that no agent selectively activates or blocks any Kv 7.2–7.5 subunit, although some compounds such as ML213 have a slightly greater potency on some Kv 7 subunits over others. In summary, Kv 7 modulators have enabled the physiological role of these channels to be deciphered with some assurance. Moreover, the pharmacological discrimination of Kv 7.1 from other subunits raises the possibility that the contribution of Kv 7.1 versus other Kv 7s in different cellular scenarios can be identified. However, the ability to separate the impact of individual www.annualreviews.org • Therapeutic Targeting of KCNQ Channels


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Kv 7.2–7.5 subunits pharmacologically needs further refinement of existing compounds and reinforcement with molecular interference techniques (44, 53).

5. LOCALIZATION AND PHYSIOLOGICAL ROLES


Kv 7 channels have a relatively negative voltage dependence (see Table 1) compared to other Kv channels, meaning that small depolarization will lead to channel opening and subsequent K+ efflux. Unlike most Kv channels, Kv 7s exhibit little or no inactivation, so they can contribute to constitutive membrane properties, including maintenance of the resting membrane potential. Moreover, the relatively slow opening (Table 1) means Kv 7 channels are effective at repolarizing action potentials. Kv 7 channels are not uniformly expressed across the body, and individual subunits have greater physiological impact in certain cell types. Kv 7.1 has a well-defined role in cardiac myocytes in association with KCNE1 (65). Kv 7.1/KCNE1 combinations are also found in the cochlea, where they contribute markedly to the K+ -rich endolymph of the stria vascularis (66). Kv 7.1/KCNE1 protein complexes mediate a countercurrent in renal proximal tubules (67) and dictate electrolyte balance in the gastrointestinal tract (68, 69). In addition, Kv 7.1, in association with KCNE3, provides the driving force for Cl− flux in colonic crypt cells, pancreatic acinar cells, and airway epithelium (70, 71). A Kv 7.1/KCNE2 protein complex governs iodide uptake and thyroxine production in thyroid cells (72, 73). Kv 7.1 expression has also been detected in vascular smooth muscle cells from many rodent and human arteries, but its role in this cell type is more enigmatic (53). Kv 7.2/7.3 channels are robustly expressed in central, peripheral, and sensory neurons, where they underlie the M current (see Section 6.2) and are also present in skeletal muscle (74). Kv 7.4 is expressed in the cochlea, where it is essential for normal hearing (75), and many congenital deafness are due to mutations to KCNQ4. In addition, Kv 7.4 is a major functional regulator in numerous smooth muscle tissues (see Section 6.3). Upregulation of Kv 7.4 expression has likewise been implicated in skeletal muscle differentiation (76). More recently, Kv 7.4 has been detected in cardiac mitochondria (77). Kv 7.5 is located in neurons, where it mainly contributes to delayed afterhyperpolarization (78); in skeletal muscle (74, 79); and in vascular and nonvascular smooth muscle. In arterial smooth muscle, there is evidence that Kv 7.5 proteins are complexed with Kv 7.4 (80, 81).

6. MAIN KV 7 PATHOPHYSIOLOGY Kv 7 channels participate in the regulation of the physiology of several cell types. Here we focus on the tissue and organs for which Kv 7’s role has been most extensively studied. Figure 2 provides an overview of the role and examples of major regulators in neurons, cardiomyocytes, and smooth muscle cells, and Table 2 summarizes the possible new avenues for therapeutic intervention targeting Kv 7 channels.

6.1. Heart Kv 7.1, in association with KCNE1 proteins, underlies IKS , the slow component of the delayed rectifier current observed during the late repolarizing phase of cardiac action potential (33, 34, 65). Activation of IKS during the plateau phase counterbalances Ca2+ influx, thus contributing to cardiac repolarization. Under normal cardiac pacing, IKS has a minor role in ventricular repolarization and in the determination of action potential duration (APD), but when heart rate increases, such as during sympathetic stimulation, the slow rate of activation and deactivation of the Kv 7.1/KCNE1 channels has a higher impact on these parameters (82). Moreover, β-adrenoceptor stimulation 26.8

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augments IKS through the modulation of protein kinase A (PKA), AKAP 9 (yotiao), adenylate cyclase isoform 9, and phosphodiesterases, which are clustered around Kv 7.1 (Figure 2) (83, 84), thus counterbalancing the increase in inward Ca2+ current and shortening the cardiac APD (85). Therefore, alteration of IKS leads to prolongation of APD that predisposes to arrhythmias (86). IKS has been recorded in rabbit, dog, and guinea pig hearts as well as human cardiac samples (87), and the magnitude of IKS is species dependent and affected by anatomical location (larger in epicardium and endocardium than in mid-myocardium, right versus left ventricle, base versus apex) (88). Cardiac myocytes also express Kv 7.4, which is selectively localized in the mitochondrial inner membrane and contributes to the regulation of mitochondrial membrane potential (77). 6.1.1. Diseases. Mutations of KCNQ1 and KCNE1 underlie many hereditary disorders of cardiac electrical activity that manifest with prolongation of the QT interval in ECG recordings owing to delayed ventricular repolarization that can lead to severe arrhythmias and sudden cardiac death (89, 90). Romano-Ward syndrome is the most common form of inherited long QT syndrome, affecting an estimated 1 in 7,000 people worldwide. It is caused by ∼500 mutations of KCNQ1 and 30 mutations of KCNE1 genes. At least 16 KCNQ1 pathological variants are associated with the autosomal recessive Jervell and Lange-Nielsen syndrome. Mutations to KCNQ1 or KCNE1 have several outcomes. Alterations in the amino acid sequences in either the PD (Kv 7.1) or the auxiliary subunit (KCNE1) produce channels that are relatively insensitive to voltage, either because of changes in the voltage sensor per se or through reduced binding of PIP2 that heightens voltage sensitivity (82). Mutations in the distal part of KCNE1 impact considerably on the response to PKA, correlating with impaired response to sympathetic nerve stimulation (82). Alternatively, KCNQ1 mutations can lead to aberrant channel assembly (91) or reduced membrane abundance (92). In the latter case, there are examples of KCNQ1 mutations that disrupt normal endosomal recycling of the channel (93) or lead to its retention in the endoplasmic reticulum (ER) (92). Interestingly, a variant associated with autosomal-dominant Romano-Ward syndrome (E261K) not only causes the retention of mutated subunits in the ER but also arrests the forward trafficking of wild-type Kv 7.1 proteins (92). In contrast, a mutation associated with the autosomal recessive Jervell and Lange-Nielsen syndrome (L51H) causes channel accumulation in the ER but does not affect wild-type Kv 7.1 (94). Gain-of-function mutations to KCNQ1 and KCNE1 also underlie many hereditary short QT syndromes characterized by truncated APD, as well as familial atrial fibrillation (95, 96). The majority of these mutations are in the VSD and lead to a constitutively active channel with little deactivation (82). Interestingly, mutations of Kv 7.1 at certain residues at the external edge of S1 result in a loss-of-function channel when coexpressed with KCNE1 but a gain-of-function channel when expressed with KCNE2 (97), showing that precise alterations in the molecular structure can have considerable and distinctive effects on IKS . 6.1.2. Therapeutic potential. IKS blockade may be a therapeutic target for arrhythmias, as the slow rate of deactivation means that current accumulates at higher cardiac pacing. In addition, Kv 7.1 specific blockers theoretically offer promise in familial atrial fibrillation caused by gain-offunction mutations to KCNQ1 or KCNE1. Interestingly, HMR1556 is more potent on currents produced by the overexpression of Kv 7.1 with a gain-of-function mutation than wild-type channels (98). Offsetting these positive actions is the knowledge that inhibition of IKS in ventricular muscle will reduce repolarization reserve and increase the likelihood of re-entrant arrhythmia, as in type 1 congenital long QT syndrome. Indeed, Towart et al. (99) argued that IKS blockade as well as the standard hERG (IKR ) screen should be considered mandatory for new drug development because of the likelihood of precipitating ventricular fibrillation. Although plasmalemmal Kv 7.1/KCNE1 channels may not offer much clinical benefit, targeting the Kv 7.4 in cardiac www.annualreviews.org • Therapeutic Targeting of KCNQ Channels


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mitochondria may have therapeutic mileage. In rat hearts, retigabine attenuated the cell death and functional impairment induced by ischemia, suggesting that activation of mitochondrial Kv 7.4 may be cardioprotective (77). Moreover, Kv 7 channels are located in the smooth muscle of coronary arteries, where they have a functional impact both at rest and in ischemia-reperfusion injury (100, 101). Consequently, enhancing Kv 7.4 may offer considerable benefit in reducing coronary underperfusion and limiting infarct size following an ischemic episode.


6.2. Brain In most neurons of the central nervous system (CNS) as well as peripheral nerves, the dominant Kv 7 subunits are Kv 7.2, Kv 7.3, and Kv 7.5. Kv 7.4 has not been detected in peripheral and sensory nerves (102) and is rarely detected in the CNS except for in neurons of the acoustic pathway, dopaminergic neurons of the mesolimbic or nigrostriatal pathway, and serotoninergic neurons of the dorsal raphe (103). Kv 7.1 transcripts have not been identified in nervous tissue. Kv 7 channels are localized to key neuronal sites, including the perisomatic region, the axon initial segment (AIS), the node of Ranvier, and the nerve terminals (see 9) (Figure 2). Targeting to different subcellular locations is obtained through interaction with specific proteins. The best studied are Kv 7.2/7.3 subunits that localize with voltage-gated sodium channels to the AIS via ankyrin G (AnkG) (Figure 2) (104). An ∼80–amino acid interaction domain for the adaptor protein AnkG has been identified at the distal end of the C terminus of Kv 7.2 and Kv 7.3 but not for other Kv 7 subunits. However, mutation of the AnkG binding site does not completely abolish the targeting of Kv 7 channels to the AIS, suggesting that additional sites or interactors are required (105). Modulation of AnkG/ Kv 7 binding also regulates Kv 7 channel localization and thus neuronal activity. For instance, Kv 7.2/7.3 interaction with AnkG is enhanced by protein kinase CK2–mediated phosphorylation, which locks Kv 7.2/7.3 channels at the AIS (106). AnkG is also responsible for the internalization of Kv 7.2/7.3 heteromers in response to neurotransmitter stimulation, a mechanism contributing to AIS plasticity (107). Kv 7.2/7.3 localization at the AIS is also altered by fibroblast growth factor 14, which regulates voltage-gated Ca2+ channel expression in the same region (108) and is dependent on CaM binding (18). 6.2.1. Physiological role. Generation of action potentials in neurons is controlled by the Mcurrent (or IKM ), which exhibits slow activation kinetics and relatively little inactivation, resulting in considerable hyperpolarizing sink to oppose depolarizing surges. Therefore, IKM activation results in a generalized silencing of the neuron, especially after sustained depolarizing stimuli, when it limits spike duration and consequent transformation to high-frequency action potential bursts (109). IKM is so called because the initial study in sympathetic neurons showed it was suppressed by muscarinic receptor stimulation; however, most stimulatory receptors coupled to Gq inhibit IKM (reviewed in 13). A considerable amount of research involving studies on ion channel expression profiles, comparative electrophysiology, and sensitivity to blocking agents has led to the acceptance that M-channels are mainly Kv 7.2/7.3 heteromers (110–114). Kv 7.5 also forms heteromers with Kv 7.3, but the resultant channel has a less negative voltage dependence and current amplitude than Kv 7.2/7.3 heteromers. As such, Kv 7.5 contributes to IKM heterogeneity by sequestering Kv 7.3 subunits, reducing the availability to form the more efficient Kv 7.2/7.3 heteromers (78). As neuronal Kv 7 channels effectively function in a similar capacity, the neurophysiological outcome of Kv 7 channel opening therefore depends on the subcellular localization. Thus, perisomatic Kv 7 channels, by opening in response to sustained trains of action potentials, reduce the frequency of neuronal firing (spike-frequency adaptation) and contribute to the medium component of the afterhyperpolarization current, which determine the neuron refractory 26.10

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period (115–117). Kv 7-mediated currents also contribute to the slow afterhyperpolarization and the hippocampal membrane potential oscillation known as theta resonance, which are important for synaptic plasticity and memory (78, 118). In contrast, axonal Kv 7 channels prevent aberrant spontaneous firing, whereas Kv 7 channels in the nerve terminals modulate neurotransmitter release (119). Paradoxically, Kv 7 activation in the axon can increase action potential amplitude as sodium channel inactivation becomes alleviated by the membrane hyperpolarization generated (120). Irrespective of the nuances, Kv 7 channels (and particularly Kv 7.2/7.3) have pronounced effects on different neuronal types in diverse brain areas. 6.2.2. Diseases. Although KCNQ2 and KCNQ3 genes were identified and cloned because of their association with an inherited benign form of epilepsy of the newborn (110–112), variants in the KCNQ2 gene are responsible for a wide spectrum of phenotypes characterized by hyperexcitability, ranging from mild and self-limiting epilepsy [benign familial neonatal epilepsy (BFNE)] to severe epileptic encephalopathy with cognitive impairment, neuroradiological alterations, and pharmacoresistant seizures [neonatal epileptic encephalopathy (NEE)] (27). Variants in KCNQ3 have also been described but are associated only with BFNE. Such heterogeneity is partly explained by different mutations affecting different domains of Kv 7.2 channels. Mutations affecting the voltage dependence (121), interaction with PIP2 (122), or subcellular localization at key neuronal sites (123) are associated with more severe phenotypes. This phenomenon is further highlighted by the fact that mutations in KCNQ2 have been found in a substantial proportion of patients with unexplained epileptic encephalopathy and NEE without previous seizures. In contrast, most forms of BFNE are explained by the loss of channel function (haploinsufficiency) (27). In line with the heterogenous spectrum, mutations in KCNQ2 are associated with myokymia (124). Alteration of Kv 7 channel activity is also involved in brain ischemic injury (125), age-related impairment of memory (126), stress-related dysfunction of the neuroendocrine system (127), addiction (128), and neuronal differentiation (129). 6.2.3. Therapeutic potential. Activation of IKM is one of the latest strategies to treat epilepsy. Retigabine (ezogabine) has been approved as add-on therapy in partial-onset seizures. Opening of Kv 7 channels might be particularly useful in those NEE cases in which Kv 7.2 mutations severely impair channel function (121). Moreover, modulation of IKM is a potential target in many other diseases driven by neuronal hyperexcitability, such as neuropathic pain, ischemia, and schizophrenia (130). 6.2.3.1. Neuroprotection. Retigabine and other Kv 7.2/7.3 activators prevented cell death in in vitro models of brain ischemia (131). Kv 7 activators also reduced rat brain infarct size and neurological dysfunctions when administered within 6 h after the ischemic insult, thus representing a potential valid strategy in the acute treatment of stroke (125). Extra benefit may also be derived from the identification of Kv 7 channels in the smooth muscle of the cerebral circulation that promote vasodilatation (132, 133). 6.2.3.2. Pain. Kv 7 channels are expressed in primary afferent and spinal neurons and possibly in brain areas involved in the processing of pain (134). Kv 7.2 is downregulated in rat dorsal root ganglia during neuropathic pain, and endogenous modulation of the IKM contributes to peripheral sensitization after inflammation (135). Retigabine and other Kv 7 activators are efficacious in in vitro and in vivo models of neuropathic pain but failed to show significant results in a clinical trial on postherpetic neuralgia. Defining the subunit composition of IKM in the nociceptive pathway and finding more specific drugs represent a valid therapeutic strategy. www.annualreviews.org • Therapeutic Targeting of KCNQ Channels


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6.2.3.3. Memory. Evidence for the involvement of Kv 7 channels in memory formation is conflicting. Fontán-Lozano and colleagues (136) showed that inhibition of Kv 7 channels facilitated synaptic plasticity and the memory process in certain circumstances, in line with the original use of IKM blockers such as XE-991 as a cognition enhancer. In contrast, transgenic mice with conditional suppression of IKM showed impaired spatial memory (117), and reduction of IKM mediated age-dependent memory decline (126). Moreover, flupirtine prevents stress-induced attenuation of both memory retrieval and hippocampal long-term potentiation (137). Interestingly, β-site amyloid precursor protein–cleaving enzyme (BACE1) increases IKM , and overexpression of BACE1 in Alzheimer’s disease (AD) might be an endogenous anticonvulsant mechanism to counteract hyperexcitability and subsequent neurodegeneration. In this view, Kv 7 activators rather than blockers may prevent cognitive dysfunction in AD (138). 6.2.3.4. Psychiatric disorders. Kv 7 modulators regulate dopamine release and modulate dopamine-neuron firing in the ventral tegmental area that is associated with reward mechanisms, raising the possibility of using Kv 7 modulators in the treatment of schizophrenia, drug abuse, and anxiety. More recently, Kv 7.3/7.5 dysfunction has been associated with autism (139), and Kv 7.2/7.3 in the nucleus accumbens is altered by chronic alcohol intake (128). Kv 7 channel activation is effective in different models of stimulant and alcohol abuse (128) as well as various models of mania (140) and anxiety (141). Finally, overexpression of Kv 7.3 in the ventral tegmental area normalizes depressive phenotype, and Kv 7 activators possess antidepressant activity, possibly via the potentiation of resilience (capacity to cope with stress) mechanisms (142).

6.3. Smooth Muscle Smooth muscle cells are nonstriated, contractile cells that underlie a host of involuntary actions, including blood pressure, airflow, gastrointestinal motility, micturition, and reproductive function. Smooth muscles are either mechanically quiescent (e.g., arteries, trachea) or exhibit spontaneous contractions driven by depolarizing slow waves and fast action potentials (e.g., bladder, uterus, regions of the gastrointestinal tract). Much of the contractile activity of smooth muscles is mediated by influx of Ca2+ through voltage-dependent Ca2+ channels. Active Kv 7 channels produce membrane hyperpolarization sufficient to reduce the likelihood of Ca2+ channel opening and hence attenuate vasoconstrictor responses (143, 144). In phasically active smooth muscles such as the bladder, Kv 7 channel–mediated hyperpolarization suppresses depolarization surges and reduces action potential discharge, akin to the role of this channel in neurons. This leads to a marked reduction in the frequency of spontaneous contractions (145–148). Transcripts for KCNQ genes have been detected in the smooth muscle from many rodent and human arteries, including mesenteric, renal, cerebral, coronary, gracilis, penile, and visceral adipose smooth muscle, as well as throughout the gastrointestinal tract, uterus, corpus cavernosum, airway, and bladder (45, 146–153). In arteries, Kv 7.1, Kv 7.4, and Kv 7.5 are well expressed, whereas Kv 7.3 expression is sporadic and Kv 7.2 negligible (52). A functional role for Kv 7 proteins was established using pharmacological agents in whole-artery studies allied to single-cell electrophysiology. In arterial smooth muscle, pan-Kv 7 blockers such as XE991 or linopirdine produce membrane depolarization, inhibit a sustained K+ conductance, and either contract arteries at rest or enhance receptor-mediated vasoconstriction (44, 80, 100, 143, 151, 154–156). In contrast, Kv 7.1-specific blockers (see Table 2) have no effect on arterial tone (80, 157), suggesting Kv 7.4 and Kv 7.5 are more relevant functionally, which is supported by work involving molecular knockdown of Kv 7 proteins (44, 80). Activators of Kv 7 channels, irrespective of the subunit selectivity (see Table 2), are effective relaxants of precontracted arteries and suppress vasoconstrictor responses (e.g., 44, 80, 100, 26.12

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143, 151, 154, 155, 158). These effects are associated with membrane hyperpolarization and augmented K+ currents in patch clamp studies, although the magnitude of the changes is rather small compared to the whole-artery effects of these agents. However, the high resistance of smooth muscle means that small changes in current flow can produce large changes in membrane voltage. Kv 7 channel inhibition increases the spontaneous contractility of phasic tissues of the gastrointestinal tract, bladder, and uterus, whereas Kv 7 channel activators decrease these events (146–150). Based upon proximity ligation assay studies and the relative effect of Kv 7.1-specific versus pan-Kv 7 blockers, the dominant functional species in arteries seems to be a Kv 7.4/7.5 heteromer (80, 159). Similar molecular insight is lacking for visceral smooth muscles, but pharmacological effects in these smooth muscles mirror those seen in arteries (147, 148). In vivo studies provide further evidence of the importance of Kv 7 channels in smooth muscle control: Retigabine treatment results in dose-dependent hypotension in rats and reduces basal and maximal bladder pressure (52, 143). In addition, linopirdine increases pulmonary artery pressure without apparently affecting systemic pressure (160). In addition to their role in maintaining relaxed smooth muscles, there is considerable evidence that Kv 7 channels are among the functional endpoints for many receptor vasorelaxants, including Gs-linked G protein–coupled receptor agonists (e.g., isoproterenol, adenosine, calcitonin gene-related peptide) signaling through PKA/AKAP or exchange protein activated by cyclic AMP (EPAC)/RAP, depending on the artery (80, 81, 161), as well as guanylate cyclase–coupled natriuretic peptide receptors (155). Kv 7 channels are also functional components of vasopressininduced vasoconstriction, especially at low concentrations at which protein kinase C–elicited inhibition of Kv 7 channels and subsequent depolarization increases opening of voltage-gated Ca2+ channels (158, 162). It is possible that tweaking Kv 7 activity can embellish endogenous receptormediated responses to elicit therapeutic effect. This step necessitates a greater understanding of the complexities of post-receptor signal interaction with Kv 7 channels. Overall, the past decade has provided considerable evidence for Kv 7 channels as master regulators of smooth muscle activity. However, there are a couple of caveats to these observations. First, except for the uterine studies, the current understanding of Kv 7 channels in smooth muscle has been derived from males, and there may be sex differences in the impact of Kv 7 channels. Indeed, Kv 7.4 protein is higher in mesenteric arteries from female mice compared to males (45). Second, most visceral smooth muscles contain interstitial cells that functionally modulate smooth muscle activity, and information on Kv 7 channels in these cells is scarce (145).

6.3.1. Role of KCNE subunits. KCNE expression products alter the pharmacology, biophysical attributes, and trafficking of Kv 7 channels and may have considerable impact on smooth muscle activity. All KCNEs are expressed in arteries, with KCNE4 being the most abundant (44, 163), and in rat mesenteric arteries, KCNE4 protein colocalizes with Kv 7.4/7.5 (64). No pharmacological modulators of KCNE proteins are available, but morpholino-mediated suppression of KCNE4 translation reduced the membrane abundance of Kv 7.4, depolarized the membrane potential, decreased Kv 7-dependent currents, and increased contractility (44), suggesting that KCNE4 protein plays a key role in smooth muscle physiology via altered Kv 7.4 contribution. In support of this, mesenteric arteries from male and female KCNE4 knockout mice have impaired relaxations to isoproterenol and the Kv 7 activator ML213 (65). KCNE expression has also been identified in the uterus and bladder. In the uterus, all KCNEs are expressed and KCNE1 increases during metestrus (148). In uteri from pregnant mice, KCNE2 and KCNE4 are significantly upregulated, whereas KCNE1, KCNE3, and KCNE5 are downregulated (149, 164). The functional consequences of these changes are unknown. www.annualreviews.org • Therapeutic Targeting of KCNQ Channels


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6.3.2. G protein βγ subunits and Kv 7 channels. Gβγ, most commonly associated with the heterotrimeric G protein–coupled receptor complex, are well-known activators of inward-rectifying K+ channels in the heart (165). Kv 7.4 channels, and native vascular Kv 7 channels in the renal artery, are also positively regulated by Gβγ (166). Strikingly, Gβγ inhibitors reduced Kv 7.4 and native Kv 7-dependent currents, suggesting these channels have a basal requirement of the activity of Gβγ for their own voltage-dependent activity. In the renal artery, Gβγ inhibitors produce contractions and inhibit isoproterenol-dependent relaxations to a similar degree as linopirdine. Kv 7 channels in smooth muscle are affected by a battery of cellular signals, and future work investigating how different entities interrelate and modulate function in different smooth muscle tissues is paramount. It will be crucial to evaluate not only the pathological role of the ion channel but also the impact of these known regulators on the disease (52, 143).

6.4. Pathogenesis Unlike the heart and brain, there is no hereditary disorder of smooth muscles that can be pinpointed to mutation of KCNQ genes. However, Kv 7 dysfunction has been identified in disorders including hypertension and erectile dysfunction (ED) and may underlie many other smooth muscle disorders. As such, modulating Kv 7 activity or targeting the processes that alter Kv 7 trafficking are potential therapeutic targets for the treatment of overactive bladder, preterm labor, gastrointestinal dysfunction, and asthma (51, 52, 143). 6.4.1. Vascular disease. Kv 7.4 expression is reduced in various arteries from spontaneously hypertensive rats (SHRs) and angiotensin II–infused mice (154). Interestingly, in SHRs, Kv 7.4 downregulation is mediated by a specific small regulatory RNA (microRNA or miR), namely miR153, that seems to contribute to the hypertensive phenotype (167). miR190-dependent regulation of Kv 7.5 has also been implicated in hypoxic pulmonary vasoconstriction (168). Kv 7 dysfunction is also observed in diabetes-related coronary artery disease. Left coronary arteries (LCAs) treated with high glucose have smaller Kv 7-dependent currents and are less responsive to Kv 7 channel activators (101). LCAs from type 1 diabetic mice also have impaired Kv 7-dependent responses. These differences are not seen in the right coronary artery, which has a much lower expression of Kv 7 channels and less Kv 7-dependent current. The negative effects of high glucose on Kv 7 channel function are reversed with treatment by the peroxisome proliferator-activator receptor β/δ inhibitor GW0742, indicating a role for this pathway in diabetes-related coronary artery disease (169). 6.4.2. Erectile dysfunction. Kv 7 channels are present and functionally active in the penile arteries and corpus cavernosum of rats, where they contribute to nitric oxide–dependent relaxations, which mediate penile erection (153). ED is common in cardiovascular diseases, especially in association with diabetes, and in a model of metabolic syndrome (SHRs, which are prone to heart failure), both KCNQ4 and KCNQ5 transcript levels were significantly decreased in the corpus cavernosum. This was associated with an ablation of Kv 7-dependent relaxations and the Kv 7 component of nitric oxide–stimulated relaxations. This raises the possibility of Kv 7 enhancers as treatment for ED, maybe in combination with phosphodiesterase inhibitors.

7. FUTURE DIRECTIONS The Kv 7 world has blossomed since the original identification of KCNQ1 in 1996. Kv 7 channels now have accepted roles in neuronal, cardiac, epithelial, and smooth muscle cells. Moreover, 26.14

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several entities that regulate Kv 7 channels at different levels have been identified. For the future, there is a pressing need to develop modulators of specific Kv 7 subunits to allow for tissue-specific treatments. Moreover, the impact of KCNE subunits on Kv 7 channels other than Kv 7.1 and outside the cardiac myocyte needs to be addressed. Next-generation therapeutics could target the KCNE subunit to modify cellular activity. Alternatively, addressing the mechanisms dictating channel activity both in situ and de novo opens a rich vein of possible therapeutic angles and greater understanding of cellular physiology.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS I.A.G. is supported by research funds from the British Heart Foundation (grants PG/12/63/29824 and PG/15/97/31862) and the Medical Research Council UK (grant MR/K019074/1).

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Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets: Promise and Pitfalls.

TRP Channels as Therapeutic Targets in Diabetes and Obesity.

Epigenomes as therapeutic targets.

Potassium channels and airway function: new therapeutic prospects.

Atomic basis for therapeutic activation of neuronal potassium channels.

DNA ligases as therapeutic targets.

Mitochondrial ion channels as oncological targets.

Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets.

Acid-sensing ion channels: potential therapeutic targets for neurologic diseases.

Ca(2+)-activated K(+) channels as therapeutic targets for myocardial and vascular protection.

Integrins as Therapeutic Targets for Respiratory Diseases.

Angiotensins as therapeutic targets beyond heart disease.

Identifying cancer mutations as therapeutic targets.

MicroRNAs as therapeutic targets in atherosclerosis.

Protein tyrosine phosphatases as potential therapeutic targets.

Cytokines as therapeutic targets in skin inflammation.

MicroRNAs as therapeutic targets in human cancers.

Enhancer-associated RNAs as therapeutic targets.

Matrix metalloproteinases as therapeutic targets for stroke.

Protein kinases as cardiovascular therapeutic targets.

Integrins as Therapeutic Targets: Successes and Cancers.

Mitochondrial potassium channels as pharmacological target for cardioprotective drugs.

Potassium channels as multi-ion single-file pores.

Structure of potassium channels.