Amitriptyline Is a Potent Blocker of Human Kv1.1 and Kv7.2/7.3 Channels

Punke, Mark A.; Friederich, Patrick

doi:10.1213/01.ane.0000260310.63117.a2

Cited by 33 publications

(28 citation statements)

References 36 publications

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“…Next we assayed the effect of the widely prescribed tricyclic antidepressant amitriptyline, a Kv7.3 channel blocker shown to act from the extracellular side (35), on the single channel currents of the Kv7.3 PM. Injection of 10 M amitriptyline in the cis compartment (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine

Syeda

Santos

Montal

2016

Journal of Biological Chemistry

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KCNQ (voltage-gated K؉ channel family 7 (Kv7)) channels control cellular excitability and underlie the K ؉ current sensi- Members of the voltage-gated K ϩ (Kv) 5 channel family 7 (Kv7, otherwise known as KCNQ) are key determinants of cellular excitability in the heart (Kv7.1) and brain (Kv7.2-7.5) (1, 2). There is no crystal structure for any member of Kv7 family, although they constitute prominent targets of clinically relevant drugs, and their dysfunction is implicated in a number of human diseases (1-3). In their physiological context, Kv7 channels open at subthreshold voltages and are modulated by G protein-coupled receptor signaling pathways via secondary messengers (1, 2). In neurons, Kv7.2/3 heteromers presumably underlie the K ϩ current sensitive to muscarinic receptor signaling, the M current (4 -7). Mutations in the Kv7.2 (8 -11) and Kv7.3 (11,12) subunits underlie a form of inherited human epilepsy: benign familial neonatal convulsions. Retigabine (RTG,methylamino]phenyl]carbamate), an anticonvulsant drug approved for the adjunctive treatment of partial-onset seizures in adults, is thought to act primarily by increasing the propensity to reside in the open conformation of neuronal Kv7.2/3 channels (13-15), leading to hyperpolarization of the membrane potential toward the K ϩ equilibrium potential and, therefore, attenuating the repetitive firing pattern that underlies seizures (16 -19). However, the molecular mechanism by which RTG opens the Kv7.2/3 channels is not well understood. Remarkably, cardiac Kv7.1 channels are insensitive to RTG (15,20,21). This exquisite specificity affords an opportunity to dissect the target site of action on Kv7.2/3 channels.We selected the PM of the Kv7 (KCNQ) channel family because the amino acid sequence of its pore and voltage sensor modules is similar to that of KvLm, a bacterial Kv for which we solved the structure of the pore-only module in a lipid environment at atomic resolution (22). We exploit the structural independence of the pore and sensor modules of to produce homomers (6, 7, 13-15, 20, 21, 25-27) and heteromers (6, 7, 13-15, 20, 25-27) of Kv7.2 and Kv7.3 PMs by in vitro transcription and translation. Single-channel activity of the purified pore-only module (PM) was characterized after reconstitution in lipid bilayers. Single-channel currents through purified Kv7.2, Kv7.3, and Kv7.2/Kv7.3 PMs are K ϩ -selective and blocked by specific Kv7 channel blockers (28). Interestingly, RTG potentiates channel function by increasing single channel open probability in all functional assemblies of Kv7 PMs, validating that the site of action of RTG is embodied in the sensorless PM. Furthermore, a key mutation in Kv7.3 PM W265L renders the channel insensitive to RTG, further confirming the PM of Kv7 channels as the interaction site for the drug. Experimental Procedures

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Section: Resultsmentioning

confidence: 99%

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine

Syeda

Santos

Montal

2016

Journal of Biological Chemistry

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“…Amitriptyline inhibits the delayed potassium rectifier potassium channels Kv7.2/7.3 and Kv1.1 (EC 50 of 1.0 and 22 μ M, resp.) [376]. Additionally, amitriptyline depresses sodium current (Kd of 20 μ M) [377], as well as L-type calcium current in the heart (EC 50 of 23 μ M at a stimulation frequency of 0.33 Hz) [378].…”

Section: Sert = Net Inhibitorsmentioning

confidence: 99%

Monoamine Reuptake Inhibitors in Parkinson’s Disease

Huot

Fox

Brotchie

2015

Parkinson's Disease

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The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia.

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“…It has multimodal actions such as an anticholinergic effect, histaminergic down-regulation, gamma-aminobutyric acid (GABA)-B receptor up-regulation, α-adrenergic receptor antagonism and sodium, L-type calcium and Kv1.1, Kv7.2, and Kv7.3 voltage-gated potassium ion channel blockade [34,40,41] . Importantly, AMI is an agonist of the TrkA and TRkB receptors, so it influences the activation of the NGF and BDNF [42] .…”

Section: Amitriptyline (Ami)mentioning

confidence: 99%

Alleviation of pain in painful diabetic neuropathy

Tajti

Delia

Majláth

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Painful diabetic neuropathy (PDN) is a disabling pain condition. Its pathomechanism remains unknown, but a sensitization and neuronal hyperexcitabilty have been suggested. Only symptomatic pharmacological pain-alleviation treatment is currently available. Areas covered:The origin of PDN is enigmatic, and the evidence-based therapeutic guidelines therefore consist only of antidepressants and antiepileptics as first-line recommended drugs. This article relates to a MEDLINE/PubMed systematic search (2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015). Expert opinion:The results of the meta-analysis from the aspect of the efficacy of amitriptyline, duloxetine, venlafaxine, gabapentin and pregabalin are favorable, but the placebo response rate is relatively high in patients with neuropathic pain. For personalization of the medication of PDN patients, the optimum dosing, the genotyping of the metabolizing enzymes and optimum biomarkers are needed. As concerns the future perspectives, specific sodium channel subtype inhibitors acting on peripheral nociceptive neurons or modified Ttype voltage-gated calcium channel blockers may be promising targets for pharmaceutical innovations. Another attractive strategy for the treatment is based on the effects of monoclonal antibodies against nerve growth factor, sodium channel, specific receptor and cytokines. Botulinum toxin A, capsaicin patch and spinal cord stimulation therapies are the nearest future therapeutic options for the treatment of PDN patients.

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Amitriptyline Is a Potent Blocker of Human Kv1.1 and Kv7.2/7.3 Channels

Cited by 33 publications

References 36 publications

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine

Monoamine Reuptake Inhibitors in Parkinson’s Disease

Alleviation of pain in painful diabetic neuropathy

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