Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid

Ejneby, Malin Silverå; Wu, Xiongyu; Ottosson, Nina E.; Münger, E. P.; Lundström, I.; Konradsson, Peter; Elinder, Fredrik

doi:10.1085/jgp.201711965

Cited by 10 publications

(39 citation statements)

References 30 publications

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“…S2, S3). This mechanism is consistent with our previous results on two other resin acids (DHAA and Wu32) showing an increased G(V) shift upon mutation of R362 (Ottosson et al, 2017;Silverå Ejneby et al, 2018); illustrated in Fig. 1D.…”

Section: A S4/pore Pocket Is Important For Wu50 Effectssupporting

confidence: 93%

“…Two experimental findings support the electrostatic channel-opening mechanism: (1) The addition of two positively charged residues at the top of S4 of the Shaker KV channel [M356R/A359R (=R-1 and R0 in Fig. 1B), from hereon called the 2R motif] increases the channel-opening effect of resin acids (G(V)-shift towards more negative membrane voltages; Ottosson et al, 2014Ottosson et al, , 2015Ottosson et al, , 2017Silverå Ejneby et al, 2018). (2) Substituting the negative charge on the resin acid by a positive one promotes channel closing (G(V)-shift towards more positive membrane voltages; Ottosson et al, 2017).…”

Section: Introductionmentioning

confidence: 81%

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Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Saker channel

Ejneby

Gromova

Ottosson

et al. 2020

Preprint

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Resin acids and their derivatives open voltage-gated potassium (KV) channels by attracting the positively charged voltage sensor helix of the channel (S4) towards the extracellular leaflet of the cellular membrane and thereby favoring gate opening. The resin acids have been proposed to primarily bind in a pocket in the periphery of the channel, located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. However, neutralization of the top gating charge of the Shaker KV channel unexpectedly increases the resin-acid induced opening, suggesting other mechanisms and possibly other sites of action.Here we explored the binding of two resin-acid derivatives, Wu50 and Wu161, to the Shaker KV channel by a combination of in-silico docking, molecular dynamics simulations, and electrophysiological study of mutated channels. We identified three potential resin-acid binding sites around the voltage sensor helix S4: (1) the S3/S4 site identified in our previous work, (2) a site located in the cleft between S4 and the pore domain (the S4/pore site), and (3) a site located at the extracellular side of the voltage-sensor domain in a cleft formed by S1-S4 (the top-VSD site). The presence of multiple binding sites around S4 and the anticipated helical-screw motion of the helix during activation makes the effect of resin acid derivatives on channel function intricate. The propensity of a specific resin acid to open/close a voltagegated channel likely depends on its exact binding pose and the types of interactions it can form with the protein in a state-specific manner.

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Section: A S4/pore Pocket Is Important For Wu50 Effectssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 81%

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Saker channel

Ejneby

Gromova

Ottosson

et al. 2020

Preprint

Self Cite

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“…[29] The 3R Shaker K V channel opens at more positive membrane voltages compared to wt Shaker Kv channel (V 1/2 = −21 mV (wt), V 1/2 = 25 mV 3R. [30] Therefore, higher light intensities could be used with the 3R. Electrophysiological measurements were done 1-4 days after RNA injection, or 1 day after oocyte harvesting for uninjected oocytes.…”

Section: Methodsmentioning

confidence: 99%

Extracellular Photovoltage Clamp Using Conducting Polymer‐Modified Organic Photocapacitors

Ejneby

Migliaccio

Gicevičius

et al. 2020

Adv Materials Technologies

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Optoelectronic control of physiological processes accounts for new possibilities ranging from fundamental research to treatment of disease. Among nongenetic light‐driven approaches, organic semiconductor‐based device platforms such as the organic electrolytic photocapacitor (OEPC) offer the possibility of localized and wireless stimulation with a minimal mechanical footprint. Optimization of efficiency hinges on increasing effective capacitive charge delivery. Herein, a simple strategy to significantly enhance the photostimulation performance of OEPC devices by employing coatings of the conducting polymer formulation poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonate), or PEDOT:PSS is reported. This modification increases the charge density of the stimulating photoelectrodes by a factor of 2–3 and simultaneously decreases the interfacial impedance. The electrophysiological effects of PEDOT:PSS‐derivatized OEPCs on Xenopus laevis oocyte cells on membrane potential are measured and voltage‐clamp techniques are used, finding an at‐least twofold increase in capacitive coupling. The large electrolytic capacitance of PEDOT:PSS allows the OEPC to locally alter the extracellular voltage and keep it constant for long periods of time, effectively enabling a unique type of light‐controlled membrane depolarization for measurements of ion channel opening. The finding that PEDOT:PSS‐coated OEPCs can remain stable after a 50‐day accelerated ageing test demonstrates that PEDOT:PSS modification can be applied for fabricating reliable and efficient optoelectronic stimulation devices.

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“…Interestingly, PiMA significantly increased the sensitivity to the voltage of Kv1.1 channels possibly through a mechanism involving residues in the pore region (F322 in S5) [119]. The preclinical efficacy of compounds developed so far has not been verified and their translational potential not established; in addition, PiMA and DHAA are not Kv1 selective compounds as they can also activate other channels such as Ca 2+ -activated (BK) and Kv7.2/7.3 potassium channels [119,120]. Therefore, these structure-activity relation studies could provide initial chemical structures to design more selective Kv1.1 activators.…”

Section: Kv11-targeted Pharmacological Approachesmentioning

confidence: 99%

Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches

D’Adamo

Liantonio

Rolland

et al. 2020

IJMS

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Kv1.1 belongs to the Shaker subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. KCNA1 is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal dominant disorder characterized by ataxia and myokymia and for which different and variable phenotypes have now been reported. The iterative characterization of channel defects at the molecular, network, and organismal levels contributed to elucidating the functional consequences of KCNA1 mutations and to demonstrate that ataxic attacks and neuromyotonia result from cerebellum and motor nerve alterations. Dysfunctions of the Kv1.1 channel have been also associated with epilepsy and kcna1 knock-out mouse is considered a model of sudden unexpected death in epilepsy. The tissue-specific association of Kv1.1 with other Kv1 members, auxiliary and interacting subunits amplifies Kv1.1 physiological roles and expands the pathogenesis of Kv1.1-associated diseases. In line with the current knowledge, Kv1.1 has been proposed as a novel and promising target for the treatment of brain disorders characterized by hyperexcitability, in the attempt to overcome limited response and side effects of available therapies. This review recounts past and current studies clarifying the roles of Kv1.1 in and beyond the nervous system and its contribution to EA1 and seizure susceptibility as well as its wide pharmacological potential.

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Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid

Cited by 10 publications

References 30 publications

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Saker channel

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Saker channel

Extracellular Photovoltage Clamp Using Conducting Polymer‐Modified Organic Photocapacitors

Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches

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