Identification of Molluscan Nicotinic Acetylcholine Receptor (nAChR) Subunits Involved in Formation of Cation- and Anion-Selective nAChRs

Nierop, Pim van; Keramidas, Angelo; Bertrand, Sonia; Minnen, Jan van; Gouwenberg, Yvonne; Bertrand, Daniel; Smit, August B.

doi:10.1523/jneurosci.2015-05.2005

Cited by 63 publications

(53 citation statements)

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“…In the molluscan CNS, ACh also acts as a neurotransmitter (Walker et al, 1996), but unlike in vertebrates, the molluscan cholinergic receptors may mediate both excitatory (cathionic) and inhibitory (anionic) postsynaptic effects (Kehoe and McIntosh, 1998;van Nierop et al, 2005;Vulfius et al, 2005). The identification of the molluscan AChR binding protein AChRBP, homologue of the ligand-binding extracellular loop of the nACh receptors (Smit et al, 2001), further facilitated the comparative studies including the evolutionary relationship of the nAChRs between taxa (van Nierop et al, 2006;van Nierop et al, 2005) and also the structure-binding analysis of neonicotinoids (Tomizawa, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…The identification of the molluscan AChR binding protein AChRBP, homologue of the ligand-binding extracellular loop of the nACh receptors (Smit et al, 2001), further facilitated the comparative studies including the evolutionary relationship of the nAChRs between taxa (van Nierop et al, 2006;van Nierop et al, 2005) and also the structure-binding analysis of neonicotinoids (Tomizawa, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Neonicotinoid insecticides inhibit cholinergic neurotransmission in a molluscan (Lymnaea stagnalis) nervous system

et al. 2015

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Neonicotinoids are highly potent and selective systemic insecticides, but their widespread use also has a growing impact on non-target animals and contaminates the environment, including surface waters. We tested the neonicotinoid insecticides commercially available in Hungary (acetamiprid, Mospilan; imidacloprid, Kohinor; thiamethoxam, Actara; clothianidin, Apacs; thiacloprid, Calypso) on cholinergic synapses that exist between the VD4 and RPeD1 neurons in the central nervous system of the pond snail Lymnaea stagnalis. In the concentration range used (0.01-1 mg/ml), neither chemical acted as an acetylcholine (ACh) agonist; instead, both displayed antagonist activity, inhibiting the cholinergic excitatory components of the VD4-RPeD1 connection. Thiacloprid (0.01 mg/ml) blocked almost 90 % of excitatory postsynaptic potentials (EPSPs), while the less effective thiamethoxam (0.1mg/ml) reduced the synaptic responses by about 15 %. The ACh-evoked membrane responses of the RPeD1 neuron were similarly inhibited by the neonicotinoids, confirming that the same ACh receptor (AChR) target was involved. We conclude that neonicotinoids act on nicotinergic acetylcholine receptors (nAChRs) in the snail CNS. This has been established previously in the insect CNS; however, our data indicate differences in the background mechanism or the nAChR binding site in the snail. Here we provide the first results concerning neonicotinoid-related toxic effects on the neuronal connections in the molluscan nervous system. Aquatic animals, including molluscs, are at direct risk while facing contaminated surface waters, and snails may provide a suitable model for further studies of the behavioural/neuronal consequences of intoxication by neonicotinoids.Tihany, Hungary, July 22, 2015 Dr. Mikko Nikinmaa Editorial Office Aquatic ToxicologyDear Dr Nikinmaa, Thank you very much for your response to our manuscript submission. We gratefully thank you and our reviewers for reading the manuscript, and we appreciate all the helpful comments made.After carefully checking the Reviewers' comments we improved the manuscript on the basis of their suggestions. Please find our detailed answers to the Reviewers below. Reviewer #1:We greatly appreciate the Reviewer's comment "one of the best written manuscripts that I have reviewed" Minor points Materials and Methods How was Lymnaea saline obtained? Is this the modified HiDi saline? If not, what is HiDi?For isolating the monosynaptic components of the synaptic responses between two neurons the perfusion chamber was filled with a modified saline which reduces the polysynaptically evoked postsynaptic responses and enhances the monosynaptic component (Berry and Pentreath, 1976). This modified saline contains higher amount of divalent cations (Ca 2+ and Mg 2+ ), therefore often nicknamed as HiDi saline (Brierly et al., 1997, Sivaramakrishnan et al., 2013. We added details to the text accordingly Electrophysiological recordingThere is a Winlow 1991 anda Syed et al. 1990 (PNEC, EC50, mechanistic...) We...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neonicotinoid insecticides inhibit cholinergic neurotransmission in a molluscan (Lymnaea stagnalis) nervous system

et al. 2015

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“…nicotine and choline) and antagonists (i.e. meth-yllycaconitine, dihydro-␤-erythroidine, ␣-bungarotoxin, and ␣-conotoxin-ImI) (57). Although recorded currents are smaller, oocytes expressing the LnAChR I subunit respond equally to ACh or 5-HT applications (Fig.…”

Section: Identification Of Nachr Subunits From the Cns Of L Stagnalimentioning

confidence: 94%

Identification and Functional Expression of a Family of Nicotinic Acetylcholine Receptor Subunits in the Central Nervous System of the Mollusc Lymnaea stagnalis

Nierop

Bertrand²,

Munno

et al. 2006

Journal of Biological Chemistry

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We described a family of nicotinic acetylcholine receptor (nAChR) subunits underlying cholinergic transmission in the central nervous system (CNS) of the mollusc Lymnaea stagnalis. By using degenerate PCR cloning, we identified 12 subunits that display a high sequence similarity to nAChR subunits, of which 10 are of the ␣-type, 1 is of the ␤-type, and 1 was not classified because of insufficient sequence information. Heterologous expression of identified subunits confirms their capacity to form functional receptors responding to acetylcholine. The ␣-type subunits can be divided into groups that appear to underlie cation-conducting (excitatory) and anion-conducting (inhibitory) channels involved in synaptic cholinergic transmission. The expression of the Lymnaea nAChR subunits, assessed by real time quantitative PCR and in situ hybridization, indicates that it is localized to neurons and widespread in the CNS, with the number and localization of expressing neurons differing considerably between subunit types. At least 10% of the CNS neurons showed detectable nAChR subunit expression. In addition, cholinergic neurons, as indicated by the expression of the vesicular ACh transporter, comprise ϳ10% of the neurons in all ganglia. Together, our data suggested a prominent role for fast cholinergic transmission in the Lymnaea CNS by using a number of neuronal nAChR subtypes comparable with vertebrate species but with a functional complexity that may be much higher. Nicotinic acetylcholine receptors (nAChRs)3 belong to the Cys loop family of pentameric ligand-gated ion channels (LGICs) together with the 5-HT 3 , GABA type A/C, and glycine receptors. nAChRs consist of an extracellular ligand-binding domain (LBD), a transmembrane ion channel, and an intracellular domain (1). In the mammalian central nervous system (CNS), eight ␣-type (␣2-7 and ␣9 -10) and three ␤-type (␤2-4). nAChR subunits have been identified that selectively assemble into nAChR subtypes with different pharmacology, cation conductance, and cellular localization. In the mammalian CNS, nAChRs predominantly mediate presynaptic modulation of neurotransmitter release (for example see Ref.2) and are to a limited extent involved in direct, fast synaptic transmission (for example see Refs. 3-7). In contrast, in the molluscan CNS, the mode of fast synaptic cholinergic transmission seems to prevail. The CNS of the freshwater snail Lymnaea stagnalis consists of ϳ20,000 large and identifiable neurons, of which many were shown to express functional nicotinic acetylcholine receptors (8, 9). In particular, in well described neuronal networks, various nAChR subtypes were shown to mediate synaptic transmission (10, 11). Uniquely, molluscs possess excitatory and inhibitory nAChR subtypes conducting cations and anions, respectively (9, 12-15). Also, different excitatory and inhibitory nAChR subtypes mediate cholinergic transmission at single identified synapses, the differential contribution of which is regulated by soluble extracellular factors (11, 16). Therefore, functio...

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“…Binding of extracellular acetylcholine opens the channel, allowing the flow of ions down the electrochemical gradient. nAchRs are typically cation selective and mediate excitatory responses by depolarizing the cell, though invertebrates also express anion-selective acetylcholine-gated channels that may play a role in fast inhibitory responses [25, 26]. As with other ligand-gated channels, acetylcholine also activates a separate class of metabotropic receptors that are not ion channels, and instead act through G-protein-coupled signaling pathways.…”

Section: Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

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Identification of Molluscan Nicotinic Acetylcholine Receptor (nAChR) Subunits Involved in Formation of Cation- and Anion-Selective nAChRs

Cited by 63 publications

References 58 publications

Neonicotinoid insecticides inhibit cholinergic neurotransmission in a molluscan (Lymnaea stagnalis) nervous system

Neonicotinoid insecticides inhibit cholinergic neurotransmission in a molluscan (Lymnaea stagnalis) nervous system

Identification and Functional Expression of a Family of Nicotinic Acetylcholine Receptor Subunits in the Central Nervous System of the Mollusc Lymnaea stagnalis

Ion Channels and Drug Transporters as Targets for Anthelmintics

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