Calcium-sensing receptor: A high-affinity presynaptic target for aminoglycoside-induced weakness

Mark T. Harnett, Wenyan Chen, Stephen M. Smith

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Administration of aminoglycoside antibiotics can precipitate sudden, profound bouts of weakness that have been attributed to block of presynaptic voltage-activated calcium channels (VACCs) and failure of neuromuscular transmission. This serious adverse drug reaction is more likely in neuromuscular diseases such as myasthenia gravis. The relatively low affinity of VACC for aminoglycosides prompted us to explore alternative mechanisms. We hypothesized that the presynaptic Ca2+-sensing receptor (CaSR) may contribute to aminoglycoside-induced weakness due to its role in modulating synaptic transmission and its sensitivity to aminoglycosides in heterologous expression systems. We have previously shown that presynaptic CaSR controls a non-selective cation channel (NSCC) that regulates nerve terminal excitability and transmitter release. Using direct, electrophysiological recording, we report that neuronal VACCs are inhibited by neomycin (IC50 830 ± 110 μM) at a much lower affinity than CaSR-modulated NSCC currents recorded from acutely isolated presynaptic terminals (synaptosomes; IC50 20 ± 1 μM). Thus, at clinically relevant concentrations, aminoglycoside-induced weakness is likely precipitated by enhanced CaSR activation and subsequent decrease in terminal excitability rather than through direct inhibition of VACCs themselves.

Original languageEnglish (US)
Pages (from-to)502-505
Number of pages4
JournalNeuropharmacology
Volume57
Issue number5-6
DOIs
StatePublished - Oct 1 2009

Keywords

  • Aminoglycoside
  • Calcium-sensing receptor
  • GPCR
  • Myastheia gravis
  • Nerve terminal
  • VACC

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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