Functional modulation of a pH-sensitive ion channel by a transporter family.

Abstract

The acid-sensing ion channel 1a (ASIC1a) is a trimeric ligand-gated ion channel. Its activation by protons results in influx of Na+ and, to a lesser extent, Ca2+ before the channel rapidly desensitizes. ASIC1a-mediated currents contribute to normal brain function, including long term potentiation, which is important for learning and memory. However, elevated activity of ASIC1a has been directly implicated in the pathogenesis of numerous disorders, such as ischemic brain injury, cancer, pain and Alzheimer's disease. Recent evidence suggests that during such pathological conditions, association with protein interaction partners can affect ASIC1a activity, thereby contributing to neuronal damage and cell death. Consequently, there is an increasing interest in understanding the regulation of ASIC1a by protein-interaction partners, which remain largely enigmatic. Here, we have used a combination of mass spectrometry, biochemistry and electrophysiology to identify a family of transporters that directly interacts with ASIC1a and regulates its function. Depending on the specific transporter isoform present in the channel-transporter complex, the activation of ASIC1a is either prolonged and potentiated or decreased. We anticipate this work to offer promising starting points for therapeutic targeting of ASIC1a-containing macromolecular complexes in various diseases.