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The Journal of Neuroscience, February 4, 2004, 24(5):1013-1022; doi:10.1523/JNEUROSCI.3191-03.2004
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Cellular/Molecular
The Discovery and Characterization of a Proton-Gated Sodium Current in Rat Retinal Ganglion Cells
Sarah Lilley,1 Paul LeTissier,2 andJon Robbins3 1,3Neural Injury and Repair Group, Centre for Neuroscience Research, King's College London, Guy's Campus, London, SE1 1UL, United Kingdom, and 2Division of Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, United Kingdom
The conduction of acid-evoked currents in central and sensory neurons is now primarily attributed to a family of proteins called acid-sensing ion channels (ASICs). In peripheral neurons, their physiological function has been linked to nociception, mechanoreception, and taste transduction; however, their role in the CNS remains unclear. This study describes the discovery of a proton-gated current in rat retinal ganglion cells termed INa(H+), which also appears to be mediated by ASICs. RT-PCR confirmed the presence of ASIC mRNA (subunits la, 2a, 2b, 3, and 4) in the rat retina. Electrophysiological investigation showed that all retinal ganglion cells respond to rapid extracellular acidification with the activation of a transient Na+ current, the size of which increases with increasing acidification between pH 6.5 and pH 3.0. INa(H+) desensitizes completely in the continued presence of acid, its current–voltage relationship is linear and its reversal potential shifts with ENa. INa(H+) is reversibly inhibited by amiloride (IC50, 188 µM) but is resistant to block by TTX (0.5 µM), Cd2+ (100 µM), procaine (10 mM), and is not activated by capsaicin (0.5 µM). INa(H+) is not potentiated by Zn2+ (300 µM) or Phe-Met-Arg-Phe-amide (50µM) but is inhibited by neuropeptide-FF (50µM). Acute application of pH 6.5 to retinal ganglion cells causes sustained depolarization and repetitive firing similar to the trains of action potentials normally associated with current injection into these cells. The presence of a proton-gated current in the neural retina suggests that ASICs may have a more diverse role in the CNS.
Key words: acid-sensing ion channel; retinal ganglion cell; sodium channel; proton-gated current; retina; pH
Received July 4, 2003; revised October 28, 2003; accepted November 12, 2003.
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