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1 Molecular Nociception Group, Department of Biology, University College London, Gower Street, London WC1E 6BT, UK2 Department of Molecular Pharmacology, Roche Bioscience, Palo Alto, CA, USA3 Howard Hughes Medical Institute, Roy J and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
The molecular basis of mechanosensory transduction by primary sensory neurones remains poorly understood. Amongst candidate transducer molecules are members of the acid-sensing ion channel (ASIC) family; nerve fibre recordings have shown ASIC2 and ASIC3 null mutants have aberrant responses to suprathreshold mechanical stimuli. Using the neuronal cell body as a model of the sensory terminal we investigated if ASIC2 or 3 contributed to mechanically activated currents in dorsal root ganglion (DRG) neurones. We cultured neurones from ASIC2 and ASIC3 null mutants and compared response properties with those of wild-type controls. Neuronal subpopulations [categorized by cell size, action potential duration and isolectin B4 (IB4) binding] generated distinct responses to mechanical stimulation consistent with their predicted in vivo phenotypes. In particular, there was a striking relationship between action potential duration and mechanosensitivity as has been observed in vivo. Putative low threshold mechanoreceptors exhibited rapidly adapting mechanically activated currents. Conversely, when nociceptors responded they displayed slowly or intermediately adapting currents that were smaller in amplitude than responses of low threshold mechanoreceptor neurones. No differences in current amplitude or kinetics were found between ASIC2 and/or ASIC3 null mutants and controls. Ruthenium red (5 µM) blocked mechanically activated currents in a voltage-dependent manner, with equal efficacy in wild-type and knockout animals. Analysis of proton-gated currents revealed that in wild-type and ASIC2/3 double knockout mice the majority of putative low threshold mechanoreceptors did not exhibit ASIC-like currents but exhibited a persistent current in response to low pH. Our findings are consistent with another ion channel type being important in DRG mechanotransduction.
(Received 26 November 2003;
accepted after revision 21 February 2004;
first published online 27 February 2004)
Corresponding author J. N. Wood: Molecular Nociception Group, Department of Biology, UCL, Gower Street, London WC1E 6BT, UK. Email: j.wood{at}ucl.ac.uk
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