The Discovery and Characterization of a Proton-Gated Sodium Current in Rat Retinal Ganglion Cells

Abstract

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 I Na(Hϩ) , 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 ϩ current, the size of which increases with increasing acidification between pH 6.5 and pH 3.0. I Na(Hϩ) desensitizes completely in the continued presence of acid, its current-voltage relationship is linear and its reversal potential shifts with E Na . I Na(Hϩ) is reversibly inhibited by amiloride (IC 50 , 188 M) but is resistant to block by TTX (0.5 M), Cd 2ϩ (100 M), procaine (10 mM), and is not activated by capsaicin (0.5 M). I Na(Hϩ) is not potentiated by Zn 2ϩ (300 M) or Phe-MetArg-Phe-amide (50 M) but is inhibited by neuropeptide-FF (50 M). 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.

Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels

“…Mild acidosis and moderate activation of ASICs is expected to induce membrane depolarization and facilitate glutamate receptor-mediated excitatory neurotransmission Wemmie et al, 2002;Lilley et al, 2004). Our data show that in mouse cortical neurons, decreasing pH to 7.0 induced a membrane depolarization of ϳ20 mV.…”

“…In addition to an increase of [Ca 2ϩ ] i through ASICs, activation of ASICs has been shown to induce membrane depolarization in hippocampal and retinal ganglion neurons Lilley et al, 2004). Membrane depolarization by ASIC activation is believed to facilitate glutamate receptor-mediated excitatory neurotransmission (Wemmie et al, 2002).…”

“…Homomeric ASIC3 responds to pH drops biphasically, with a fast desensitizing current and a late sustained component (Waldmann et al, 1997b;De Weille et al, 1998). ASIC4 is highly expressed in pituitary gland (Akopian et al, 2000;Grunder et al, 2000;Lilley et al, 2004). Similar to ASIC2b, ASIC4 does not form functional homomeric channels.…”

Acid-sensing Ion Channels in Sensory Perception

“…ASICs are therefore probably not acting as general mammalian sour receptors. Almost all ASICs have also been detected in rodent retina (33)(34)(35)(36). pH fluctuations play an important role in the retina, where acidic transients are involved in the fine-tuning of visual perception.…”

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…Since all ASICs are Na + -selective channels which have a reversal potential near Na + equilibrium potential (∼ +60 mV), activations of ASICs at normal resting potentials produce exclusively inward currents which result in membrane depolarization and the excitation of neurons [33,34]. For homomeric ASIC1a channels, acid activation also induces Ca 2+ entry directly through these channels [10,12,13].…”