Functional Modifications of Acid-Sensing Ion Channels by Ligand-Gated Chloride Channels

Xuanmao Chen,John F. MacDonald,Beverley A. Orser,Paul Whissell

doi:10.1371/journal.pone.0021970

Xuanmao Chen, John F. MacDonald + Show 2 more

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Together, acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) constitute the majority of voltage-independent sodium channels in mammals. ENaC is regulated by a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that ASICs were reversibly inhibited by activation of GABAA receptors in murine hippocampal neurons. This inhibition of ASICs required opening of the chloride channels but occurred with both outward and inward GABAA receptor-mediated currents. Moreover, activation of the GABAA receptors modified the pharmacological features and kinetic properties of the ASIC currents, including the time course of activation, desensitization and deactivation. Modification of ASICs by open GABAA receptors was also observed in both nucleated patches and outside-out patches excised from hippocampal neurons. Interestingly, ASICs and GABAA receptors interacted to regulate synaptic plasticity in CA1 hippocampal slices. The activation of glycine receptors, which are similar to GABAA receptors, also modified ASICs in spinal neurons. We conclude that GABAA receptors and glycine receptors modify ASICs in neurons through mechanisms that require the opening of chloride channels.

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Extracellular protons serve as the ligand for a family of ligandgated ion channels, acid-sensing ion channels (ASICs) [1,2]
In the study reported here, we found that ASICs were modified by the activation of GABAA receptors in hippocampal neurons
Application of GABA reversibly inhibited ASIC currents (Figure 1), but this inhibition was eliminated when GABAA receptors were blocked by application of a GABAA receptor antagonist (Figure 1)

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Introduction

Extracellular protons serve as the ligand for a family of ligandgated ion channels, acid-sensing ion channels (ASICs) [1,2]. These channels are associated with various physiological and pathophysiological functions including regulation of synaptic plasticity [3], perception of pain [4], ischemic death of neurons [5] and the termination of seizures [6]. Each ASIC subunit contains a highly conserved, cysteine-rich ‘‘thumb domain’’ region, which is implicated in the regulation of channel gating [7]. There is limited evidence as to the functional consequences of chloride binding to ASICs desensitization of the ASIC1a subtype is altered by changes in extracellular chloride and mutation of the chloride-binding site abolishes this regulation [9]

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