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1 Riluzole Blocks Human Muscle Acetylcholine

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1 Riluzole Blocks Human Muscle Acetylcholine View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archivio della ricerca- Università di Roma La Sapienza RILUZOLE BLOCKS HUMAN MUSCLE ACETYLCHOLINE RECEPTORS Cristina Deflorio1, Eleonora Palma1,2, Luca Conti1, Cristina Roseti1,2, Alessia Manteca1, Elena Giacomelli3, Cristina Limatola1,4, Maurizio Inghilleri3, Francesca Grassi1 1Dept. of Physiology and Pharmacology, Sapienza University, Rome, Italy 2IRCCS San Raffaele Pisana, Rome, Italy 3Dept. of Neurology and Psychiatry, Sapienza University, Rome, Italy 4Neuromed IRCCS, Venafro (IS), Italy Running title: Riluzole blocks human muscle AChR Key words: muscle AChR; amyotrophic lateral sclerosis; riluzole Total number of words in the paper: 4250 Corresponding author: Francesca Grassi. Dip. Fisiologia e Farmacologia, Università Sapienza, P.le A. Moro 5; I-00185 Roma, Italy. e-mail: [email protected] Table of Contents category: Molecular and cellular 1 ABSTRACT Riluzole, the only drug available against amyotrophic lateral sclerosis (ALS), has recently been shown to block muscle ACh receptors (AChR), raising concerns about possible negative side-effects on neuromuscolar transmission in treated patients. In this work we studied riluzole impact on the function of muscle AChR in vitro and on neuromuscular transmission in ALS patients, using electrophysiological techniques. Human recombinant AChR composed by α1β1δ subunits plus γ or ε subunits (γ- or ε- AChR) were expressed in HEK cells or Xenopus oocytes. In both preparations, riluzole at a clinically relevant concentration reversibly reduced the amplitude and accelerated the decay of ACh-evoked current if applied before coapplication with ACh. The action on γ-AChR was more potent and faster than on ε-AChR. In HEK outside-out patches, riluzole-induced block of macroscopic ACh-evoked current gradually developed during the initial milliseconds of ACh presence. Single channel recordings in HEK cells and in human myotubes from ALS patients showed that riluzole prolongs channel closed time, but has no effect on channel conductance and open duration. Finally, compound muscle action potentials (CMAPs) evoked by nerve stimulation in ALS patients remained unaltered after a 1-week suspension of riluzole treatment. These data indicate that riluzole, while apparently safe on synaptic transmission, may affect the function of AChR expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated. ABBREVIATIONS AChR, acetylcholine receptor; ALS, amyotrophic lateral sclerosis; CMAP, compound muscle action potential; EGFP, enhanced green fluorescent protein; IACh, ACh-evoked whole-cell current; QACh, integral of ACh-evoked whole-cell current; PKC, protein kinase C. 2 INTRODUCTION Riluzole is the only drug currently registered to treat patients with Amyotrophic Lateral Sclerosis (ALS), a fatal disease due to selective degeneration of upper and/or lower motoneurones. The compound has several adverse side effects, among which asthenia, that further decrease patients' quality of life, so that a full assessment of its effects might help in devising countermeasures. Riluzole affects the function of a variety of ion channels in neurones and possibly in muscle (Bellingham et al., 2011). In particular, when co-administered with ACh, it impairs the function of recombinant mouse acetylcholine receptors (AChR), although only at very high concentrations (Mohammadi et al., 2002), well beyond the range found in patients' serum (0.5 to 5 µM; Bellingham et al., 2011). Conversely, our group recently observed a strong block of AChR function by clinically used concentrations of riluzole in human muscle preparations obtained from ALS or denervated patients, provided that riluzole was applied before the transmitter (Palma et al., 2011). Since AChRs mediate nerve- muscle communication at the neuromuscular junction and are chronically exposed to riluzole in treated patients, it becomes mandatory to understand whether or not riluzole worsens the compromised neuromuscular transmission in ALS patients, possibly elucidating this effect at the molecular level. ALS patients experience muscle denervation and reinnervation through collateral sprouting of healthy motor neurones (Eisen and Swash, 2001), which, among many other consequences, affects the composition and distribution of muscle AChR. In innervated fibres, receptors formed by the α1β1εδ subunits (ε-AChR) are densely packed at the endplate and at the myotendineous junction and virtually absent elsewhere (Katz and Miledi, 1964). In denervated muscle cells, AChRs are formed by α1β1γδ subunits (γ-AChR), with an almost uniform distribution over the entire sarcolemma (Witzemann et al., 1991). In ALS patients, both ε- and γ-AChR are present, reflecting the presence of denervated muscle fibres. In this work we prove that in vitro riluzole has differential effects on recombinant human γ- or ε-AChR and provide a characterization of its action at the single channel level in transfected cells and in myotubes derived from ALS patients. Moreover, we analyze the effect of riluzole on nerve-muscle transmission in ALS patients before and during a brief suspension of riluzole treatment, reaching the important conclusion 3 that treatment does not impair compound muscle action potential (CMAP) generation upon repetitive nerve stimulation. MATERIALS AND METHODS Patients recruitment and analysis Thirty-six patients (14 females) with probable or definite ALS according to El Escorial criteria were recruited and analyzed at the ALS centre of Policlinico Umberto I, Università Sapienza of Rome. Their mean age was 64.5 years (range: 47- 78 years). CMAPs were recorded from the abductor digiti minimi and deltoid muscles, by ulnar nerve stimulation at the wrist and axillary nerve at Erb's point, respectively. The amplitudes of the initial negative peaks of the CMAPs were measured and the changes in CMAPs amplitude were analyzed. Repetitive nerve stimulation test was performed on the axillary nerve and the ulnar nerve, with the recording electrode over the deltoid muscle and the abductor digiti minimi muscle, respectively. For each train of repetitive stimuli, the amplitudes of the first and fifth CMAPs were compared, and the resulting decrement of the latter expressed as percentage of the first. All patients were examined before and after a 1-week suspension of riluzole treatment; data values were compared using paired Student’s t- test. Results were considered to be significantly different when p < 0.05. Needle biopsy was performed as previously described (Palma et al., 2011). The study was authorized by the Ethical Committee of Sapienza University and written informed consent to participate in the study was given by all patients. Cell culture and AChR expression in cells and oocytes AChR subunit cDNAs in pRBG4 were kindly provided by Dr A.G. Engel (Mayo Clinic, Rochester, USA). Human embryonic kidney 293 (HEK) cells were grown in Dulbecco's modified Eagle's medium (DMEM) plus 10% foetal bovine serum (both from Invitrogen, Carlsbad, CA) and 1% penicilline / streptomycine. Cells were plated on poly-L- lysine-coated 35 mm Petri dishes and transiently transfected 24 h later using Lipofectamine 2000 (Invitrogen), adding to each dish 1 µg of each subunit cDNA 4 plus 0.5 µg cDNA encoding enhanced green fluorescent protein (EGFP). HEK cells were mechanically dissociated and replated onto glass coverslips 24 h before measurements. Routinely, cells were used for electrophysiological experiments 48 to 72 h after transfection, as previously reported (Di Angelantonio et al., 2011). Cultures were maintained in a humidified incubator with 5% CO2, 37 °C. Human satellite cells were derived from muscle needle biopsies performed on ALS patients, with their written informed consent. Cells were cultured as previously described (Fucile et al., 2006; Palma et al. 2011); differentiation was induced at approximately 50% confluence by switching to a low-serum medium (DMEM plus 2% horse serum and P/S). Preparation of Xenopus laevis oocytes and nuclear injection procedures were as detailed elsewhere (Miledi et al. 2006). Oocytes were collected under anaesthesia from frogs that were humanely killed after the final collection. Patch clamp recordings in cultured cells Currents were recorded at room temperature (23-27o C) via an Axopatch 200B amplifier (Molecular Devices, Union City, CA, USA), using pCLAMP9 (Molecular Devices). In whole-cell and outside-out recordings cells were continuously superfused using a gravity-driven fast exchanger perfusion system (RSC-200, Bio-Logic, France). Whole-cell recordings were performed in standard external solution containing (mM): 140 NaCl, 2.8 KCl, 2 CaCl2, 2 MgCl2, 10 HEPES/NaOH, 10 glucose, pH 7.3. Patch pipettes (2-5 MΩ tip resistance) contained (mM): 140 CsCl, 5 BAPTA, 10 HEPES-KOH, 2 Mg-ATP, 2 MgCl2, pH 7.3. The patch series resistance was compensated by 80-95% and measurements were performed at a holding potential of -60 mV, unless otherwise indicated. Outside-out recordings were performed at -80 mV using standard external medium; patch pipettes (Sylgard-coated for single-channel recordings) contained (mM): 90 CsCl 90, 50 CsF, 5 BAPTA, 10 HEPES-KOH, 2 Mg-ATP, 2 MgCl2, pH 7.3. The rise-time of the ACh-evoked currents, measured as the interval between 10% and 90% of peak amplitude ranged between 0.8 and 3 ms in outside-out recordings. Cell-attached recordings were performed using standard external solution or a KCl- based solution (mM):
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