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The Role of the Mechanotransduction Ion Channel Candidate Nanchung- Inactive in Auditory Transduction in an Insect Ear

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The Role of the Mechanotransduction Ion Channel Candidate Nanchung- Inactive in Auditory Transduction in an Insect Ear This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular The role of the mechanotransduction ion channel candidate Nanchung- Inactive in auditory transduction in an insect ear. Ben Warren and Tom Matheson University of Leicester, Department of Neuroscience, Psychology and Behaviour, University Road, Leicester, LE1 7RH, UK DOI: 10.1523/JNEUROSCI.2310-17.2018 Received: 15 August 2017 Revised: 19 January 2018 Accepted: 26 January 2018 Published: 14 March 2018 Author contributions: B.W. wrote the first draft of the paper; B.W. edited the paper; B.W. and T.M. designed research; B.W. performed research; B.W. analyzed data; B.W. and T.M. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work was supported by a Leverhulme Trust Early Career Fellowship to BW and BBSRC Research Grant BB/L02389X/1 to TM. We would like to thank Ceinwen Tilley and Paul Seear for help teaching molecular biology techniques and Jonathan Shand and Benjamin Hunt for compiling the Schistocerca gregaria transcriptome. We would also like to thank Ruben Gonzalez, Chanida Fung and Anthony Vencatasamy for locust maintenance. We thank the Biomedical Mechanical and Electronic Workshops for construction of custom devices used in this work. We would also like to thank Georgina Fenton, Jonathan McDearmid, Ian Forsythe and an anonymous friend for helpful discussions and comments on the manuscript. Corresponding author: Ben Warren, [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2310-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 Warren and Matheson. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Title 2 The role of the mechanotransduction ion channel candidate Nanchung-Inactive in auditory 3 transduction in an insect ear. 4 Running title 5 Auditory transduction in an insect ear. 6 Authors and affiliation 7 Ben Warren and Tom Matheson 8 University of Leicester, Department of Neuroscience, Psychology and Behaviour, University 9 Road, Leicester, LE1 7RH, UK 10 Corresponding author: Ben Warren, [email protected] 11 Number of pages: 37 12 Number of figures: 9 13 Number of words: Abstract 250, Introduction 646, Discussion 1483. 14 Conflict of Interest 15 The authors declare no competing financial interests. 16 Acknowledgements 17 This work was supported by a Leverhulme Trust Early Career Fellowship to BW and BBSRC 18 Research Grant BB/L02389X/1 to TM. We would like to thank Ceinwen Tilley and Paul 19 Seear for help teaching molecular biology techniques and Jonathan Shand and Benjamin 20 Hunt for compiling the Schistocerca gregaria transcriptome. We would also like to thank 21 Ruben Gonzalez, Chanida Fung and Anthony Vencatasamy for locust maintenance. We 22 thank the Biomedical Mechanical and Electronic Workshops for construction of custom 23 devices used in this work. We would also like to thank Georgina Fenton, Jonathan 1 24 McDearmid, Ian Forsythe and an anonymous friend for helpful discussions and comments 25 on the manuscript. 26 Abstract 27 Insect auditory receivers provide an excellent comparative resource to understand general 28 principles of auditory transduction, but analysis of the electrophysiological properties of the 29 auditory neurons has been hampered by their tiny size and inaccessibility. Here we pioneer 30 patch-clamp recordings from the auditory neurons of Müller’s Organ of the desert locust 31 Schistocerca gregaria to characterise dendritic spikes, axonal spikes and the transduction 32 current. We demonstrate that dendritic spikes, elicited by sound stimuli, trigger axonal 33 spikes, and that both types are sodium- and voltage-dependent and blocked by TTX. 34 Spontaneous discrete depolarisations summate upon acoustic stimulation to produce a 35 graded transduction potential that in turn elicits the dendritic spikes. The transduction current 36 of Group-III neurons of Müller’s Organ, which are broadly tuned to 3 kHz, is blocked by three 37 ion channel blockers FM1-43, streptomycin and 2-APB known to block mechanotransduction 38 channels. We investigated the contribution of the candidate mechanotransduction ion 39 channel Nanchung-Inactive – which is expressed in Müller’s Organ - to the transduction 40 current. A specific agonist of Nanchung-Inactive, pymetrozine, eliminates the sound-evoked 41 transduction current while inducing a tonic depolarising current of comparable amplitude. 42 The Nanchung-Inactive ion channels, therefore, have the required conductance to carry the 43 entire transduction current, and sound stimulation appears not to open any additional 44 channels. The application of three mechanotransduction ion channel blockers prevented the 45 pymetrozine-induced depolarising current. This implies that either Nanchung-Inactive is, or 46 forms part of, the mechanotransduction ion channel or it amplifies a relatively small current 47 (<30 pA) produced by another mechanotransduction ion channel such as NompC. 48 49 2 50 Significance statement 51 The mechanically activated ion channel underpinning hearing is not known. We have 52 pioneered intracellular patch-clamp recordings from locust auditory neurons to unravel the 53 role of the candidate mechanotransduction ion channel Nanchung-Inactive in auditory 54 transduction in insects. 55 Introduction 56 The startling variety of auditory receptors found in insects provides a rich resource for the 57 comparative analysis of auditory mechanotransduction. For instance, insect ‘ears’ have been 58 used to understand travelling waves that are necessary for frequency discrimination 59 (Nowotny et al., 2010), otoacoustic emissions (Kössl and Boyan 1998; Möckel et al., 2007) 60 that can be used to assess hearing impairment (Kemp, 2002), and the roles of specific ion 61 channels in auditory transduction (Göpfert et al., 2006). Despite these advances, 62 investigation of insect auditory transduction has been hampered by the tiny size and 63 inaccessibility of the auditory neurons. Recordings of the mechanical-to-electrical 64 transduction events that lead to spike generation in the auditory neurons themselves are 65 sparse (Hill, 1983a,b; Oldfield and Hill, 1986). These early studies revealed that quiescent 66 insect auditory neurons exhibit discrete depolarisations that are thought to represent the first 67 mechanical-to-electrical event in the dendritic cilium (Hill, 1983a). Upon acoustic stimulation 68 these discrete depolarisations summate to produce a graded transduction potential which, if 69 large enough, generates an apical spike that propagates toward the soma to elicit a larger 70 basal spike (Hill 1983b; Oldfield and Hill, 1986). 71 72 More recent attention has focused on the cilium, where transduction is thought to take place 73 and where two Transient Receptor Potential (TRP) mechanotransduction ion channel 74 candidates, NompC and the heteromer Nanchung-Inactive have been localised to the tip, 75 and the proximal cilium respectively (Gong et al., 2004; Lee et al., 2010). In Drosophila, the 76 direct coupling of auditory neurons to the antennae (which act as sound-receivers) has 3 77 allowed measurement of the coordinated opening and closing of thousands of 78 mechanotransduction ion channels in the cilia. These channel state changes are detected as 79 nonlinear mechanical displacements of the antennae during sound stimulation (Albert et al., 80 2007). In nompC mutants this nonlinear mechanical amplification is abolished but in 81 nanchung or inactive mutants it is amplified. This led to a ‘NompC model’ that postulates 82 NompC, localised to the tips of auditory neuron cilia, as the mechanotransduction ion 83 channel. In this model Nanchung-Inactive propagates a NompC-mediated depolarisation 84 along the cilium, towards the dendrite (Göpfert et al., 2006). In insects NompC is a leading 85 contender for the transduction channel. There is strong evidence that NompC subfamily 86 channels such as TRP-4, form mechanotransduction ion channels in C. elegans (Kang et al., 87 2010). Calcium signals are abolished in nompC null mutations in Drosophila sound sensitive 88 neurons (Effertz et al., 2011) and in larval multidendritic neurons (Cheng et al., 2010), and 89 finally, NompC is mechanically sensitive when expressed ectopically or in heterologous 90 cells, (Yan et al., 2013; Gong et al., 2013). 91 92 In a complementary approach, indirect measurements of the transduction current were made 93 in Drosophila using intracellular recordings of the postsynaptic giant fibre neurons onto 94 which hundreds of antennal mechanosensory neurons are electrically synapsed (Lehnert et 95 al., 2013). The sound-induced synaptic currents in the giant neurons were reduced in 96 nompC loss-of-function mutants but abolished in nanchung mutants. This implicated 97 Nanchung-Inactive as the mechanotransduction ion channel, whereas NompC was 98 postulated to regulate the tension delivered to the cilium. The electrotonically distant location 99 of the recording site in the postsynaptic neurons (rather than the auditory neurons 100 themselves)
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