title: Riluzole blocks human muscle acetylcholine receptors.
abstract: Riluzole, the only drug available against amyotrophic lateral sclerosis (ALS), has recently been shown to block muscle ACh receptors (AChRs), raising concerns about possible negative side-effects on neuromuscular transmission in treated patients. In this work we studied riluzole's impact on the function of muscle AChRs in vitro and on neuromuscular transmission in ALS patients, using electrophysiological techniques. Human recombinant AChRs composed of α(1)β(1)δ subunits plus the γ or ε subunit (γ- or ε-AChR) were expressed in HEK cells or Xenopus oocytes. In both preparations, riluzole at 0.5 μm, 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-AChRs was more potent and faster than on ε-AChRs. 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 with regard to synaptic transmission, may affect the function of AChRs expressed in denervated muscle fibres of ALS patients, with biological consequences that remain to be investigated.
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Deflorio
authors.forename: Eleonora
authors.initials: E
authors.lastname: Palma
authors.forename: Luca
authors.initials: L
authors.lastname: Conti
authors.forename: Cristina
authors.initials: C
authors.lastname: Roseti
authors.forename: Alessia
authors.initials: A
authors.lastname: Manteca
authors.forename: Elena
authors.initials: E
authors.lastname: Giacomelli
authors.forename: Myriam
authors.initials: M
authors.lastname: Catalano
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.forename: Maurizio
authors.initials: M
authors.lastname: Inghilleri
authors.forename: Francesca
authors.initials: F
authors.lastname: Grassi
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011950:Receptors, Cholinergic / Q000502:physiology*; D019782:Riluzole / Q000494:pharmacology*; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D018680:Cholinergic Antagonists; D018696:Neuroprotective Agents; D011950:Receptors, Cholinergic; D019782:Riluzole