Proton‐independent activation of acid‐sensing ion channel 3 by an alkaloid, lindoldhamine, from <i>Laurus nobilis</i>

Osmakov, Dmitry I.; Koshelev, Sergey G.; Andreev, Yaroslav A.; Dubinnyi, Maxim A.; Kublitski, Vadim S.; Efremov, Roman G.; Sobolevsky, Alexander I.; Kozlov, Sergey A.

doi:10.1111/bph.14134

Cited by 15 publications

(22 citation statements)

References 55 publications

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“…Xenopus laevis frogs () were purchased from the Koltzov Institute of Developmental Biology, RAS. Oocytes were prepared as described previously (Osmakov et al, 2018). In brief, frogs were cooled down to 2–4°C to provide anesthesia and ~200 oocytes were surgically removed from the ovarian tissue of the animals through a small incision in the abdominal wall, which then was sewn with a single stitch.…”

Section: Methodsmentioning

confidence: 99%

“…Two‐electrode voltage‐clamp recordings were performed using the GeneClamp500 amplifier (Axon Instruments) at the holding potential of −50 mV as described in (Osmakov et al, 2018). The data were filtered at 20 Hz and digitized at 100 Hz using the L780 AD converter (L‐Card).…”

Section: Methodsmentioning

confidence: 99%

“…After injection, the oocytes were kept for 2-3 days at 19°C and then up to 7 days at 15°C in ND-96 medium supplemented with gentamycin (Cat# G1264; Merck) (50 μg/mL) and containing (in mM): 96 NaCl, 2 KCl, 1.8 CaCl 2 , 1 MgCl 2 , 10 HEPES, pH 7.4. Two-electrode voltage-clamp recordings were performed using the GeneClamp500 amplifier (Axon Instruments) at the holding potential of −50 mV as described in (Osmakov et al, 2018).…”

Section: J Lindström) Cloned Between Nhei and Bamhi Sites And Lineamentioning

confidence: 99%

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Water‐soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7‐nAChR dysfunction

Шенкарев

Shulepko

Bychkov

et al. 2020

Journal of Neurochemistry

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Lynx1 is a GPI-tethered protein colocalized with nicotinic acetylcholine receptors (nAChRs) in the brain areas important for learning and memory. Previously, we demonstrated that at low micromolar concentrations the water-soluble Lynx1 variant lacking GPI-anchor (ws-Lynx1) acts on α7-nAChRs as a positive allosteric modulator. We hypothesized that ws-Lynx1 could be used for improvement of cognitive processes dependent on nAChRs. Here we showed that 2 µM ws-Lynx1 increased the acetylcholine-evoked current at α7-nAChRs in the rat primary visual cortex L1 interneurons. At higher concentrations ws-Lynx1 inhibits α7-nAChRs expressed in Xenopus laevis oocytes with IC 50 ~ 50 µM. In mice, ws-Lynx1 penetrated the bloodbrain barrier upon intranasal administration and accumulated in the cortex, hippocampus, and cerebellum. Chronic ws-Lynx1 treatment prevented the olfactory memory and motor learning impairment induced by the α7-nAChRs inhibitor methyllycaconitine (MLA). Enhanced long-term potentiation and increased paired-pulse facilitation ratio were observed in the hippocampal slices incubated with ws-Lynx1 and in the slices from ws-Lynx1-treated mice. Long-term potentiation blockade observed in MLA-treated mice was abolished by ws-Lynx1 co-administration. To understand the mechanism of ws-Lynx1 action, we studied the interaction of ws-Lynx1 and MLA at α7-nAChRs, measured the basal concentrations of endogenous Lynx1 and the α7 nAChR subunit and their association in the mouse brain. Our findings suggest that endogenous Lynx1 limits α7-nAChRs activation in the adult brain. Ws-Lynx1 partially displaces Lynx1 causing positive modulation of α7-nAChRs and enhancement 42) for the binding to the nAChR subunits, abolishes the Aβ 1-42 cytotoxic effect in the cultured cortical neurons (Thomsen et al., 2016), and prevents the long-term potentiation (LTP) blockade caused by Aβ 1-42 (Bychkov et al., 2018). Here, we investigated the ws-Lynx1 influence on cognitive processes in vivo and on the synaptic plasticity processes ex vivo. To model cognitive impairment associated with the loss of nAChR function, C57BL/6 mice were chronically treated with of synaptic plasticity. Ws-Lynx1 and similar compounds may constitute useful hits for treatment of cognitive deficits associated with the cholinergic system dysfunction.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: J Lindström) Cloned Between Nhei and Bamhi Sites And Lineamentioning

confidence: 99%

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Water‐soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7‐nAChR dysfunction

Шенкарев

Shulepko

Bychkov

et al. 2020

Journal of Neurochemistry

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“…Recent studies also identified the endogenous isoquinoline alkaloids, the precursors of endogenous morphine biosynthesis, as the non-proton ligands of ASIC3 [ 90 ]. Moreover, alkaloid lindoldhamine isolated from Laurus nobilis is another non-proton ligand of ASIC3 opening the channel under neutral or even more alkaline (pH > 7.4) conditions [ 91 ].…”

Section: Introductionmentioning

confidence: 99%

Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

2018

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BackgroundAcid-sensing ion channels (ASICs) are a group of amiloride-sensitive ligand-gated ion channels belonging to the family of degenerin/epithelial sodium channels. ASICs are predominantly expressed in both the peripheral and central nervous system and have been characterized as potent proton sensors to detect extracellular acidification in the periphery and brain.Main bodyHere we review the recent studies focusing on the physiological roles of ASICs in the nervous system. As the major acid-sensing membrane proteins in the nervous system, ASICs detect tissue acidosis occurring at tissue injury, inflammation, ischemia, stroke, and tumors as well as fatiguing muscle to activate pain-sensing nerves in the periphery and transmit pain signals to the brain. Arachidonic acid and lysophosphocholine have been identified as endogenous non-proton ligands activating ASICs in a neutral pH environment. On the other hand, ASICs are found involved in the tether model mechanotransduction, in which the extracellular matrix and cytoplasmic cytoskeletons act like a gating-spring to tether the mechanically activated ion channels and thus transmit the stimulus force to the channels. Accordingly, accumulating evidence has shown ASICs play important roles in mechanotransduction of proprioceptors, mechanoreceptors and nociceptors to monitor the homoeostatic status of muscle contraction, blood volume, and blood pressure as well as pain stimuli.ConclusionTogether, ASICs are dual-function proteins for both chemosensation and mechanosensation involved in monitoring physiological homoeostasis and pathological signals.

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“…MitTx also modulates ASIC2a pH sensitivity. Recently, lindoldhamine, an alkaloid from Laurus nobilis , was shown to activate the ASIC3 in a proton-independent form and to act as a positive allosteric modulator of human and rat ASIC3 channels ( Osmakov et al, 2018 ).…”

Section: Asicsmentioning

confidence: 99%

Protons as Messengers of Intercellular Communication in the Nervous System

Soto

Ortega-Ramírez

Vega

2018

Front. Cell. Neurosci.

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In this review, evidence demonstrating that protons (H+) constitute a complex, regulated intercellular signaling mechanisms are presented. Given that pH is a strictly regulated variable in multicellular organisms, localized extracellular pH changes may constitute significant signals of cellular processes that occur in a cell or a group of cells. Several studies have demonstrated that the low pH of synaptic vesicles implies that neurotransmitter release is always accompanied by the co-release of H+ into the synaptic cleft, leading to transient extracellular pH shifts. Also, evidence has accumulated indicating that extracellular H+ concentration regulation is complex and implies a source of protons in a network of transporters, ion exchangers, and buffer capacity of the media that may finally establish the extracellular proton concentration. The activation of membrane transporters, increased production of CO2 and of metabolites, such as lactate, produce significant extracellular pH shifts in nano- and micro-domains in the central nervous system (CNS), constituting a reliable signal for intercellular communication. The acid sensing ion channels (ASIC) function as specific signal sensors of proton signaling mechanism, detecting subtle variations of extracellular H+ in a range varying from pH 5 to 8. The main question in relation to this signaling system is whether it is only synaptically restricted, or a volume modulator of neuron excitability. This signaling system may have evolved from a metabolic activity detection mechanism to a highly localized extracellular proton dependent communication mechanism. In this study, evidence showing the mechanisms of regulation of extracellular pH shifts and of the ASICs and its function in modulating the excitability in various systems is reviewed, including data and its role in synaptic neurotransmission, volume transmission and even segregated neurotransmission, leading to a reliable extracellular signaling mechanism.

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Proton‐independent activation of acid‐sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis

Cited by 15 publications

References 55 publications

Water‐soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7‐nAChR dysfunction

Water‐soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7‐nAChR dysfunction

Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

Protons as Messengers of Intercellular Communication in the Nervous System

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