title: Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions.
abstract: In rodent sensory neurons, acid-sensing ion channel 3 (ASIC3) has recently emerged as a particularly important sensor of nonadaptive pain associated with tissue acidosis. However, little is known about the human ASIC3 channel, which includes three splice variants differing in their C-terminal domain (hASIC3a, hASIC3b, and hASIC3c). hASIC3a transcripts represent the main mRNAs expressed in both peripheral and central neuronal tissues (dorsal root ganglia [DRG], spinal cord, and brain), where a small proportion of hASIC3c transcripts is also detected. We show that hASIC3 channels (hASIC3a, hASIC3b, or hASIC3c) are able to directly sense extracellular pH changes not only during acidification (up to pH 5.0), but also during alkalization (up to pH 8.0), an original and inducible property yet unknown. When the external pH decreases, hASIC3 display a transient acid mode with brief activation that is relevant to the classical ASIC currents, as previously described. On the other hand, an external pH increase activates a sustained alkaline mode leading to a constitutive activity at resting pH. Both modes are inhibited by the APETx2 toxin, an ASIC3-type channel inhibitor. The alkaline sensitivity of hASIC3 is an intrinsic property of the channel, which is supported by the extracellular loop and involves two arginines (R68 and R83) only present in the human clone. hASIC3 is thus able to sense the extracellular pH in both directions and therefore to dynamically adapt its activity between pH 5.0 and 8.0, a property likely to participate in the fine tuning of neuronal membrane potential and to neuron sensitization in various pH environments.
authors: Institut de Pharmacologie Moléculaire et Cellulaire,  Centre National de la Recherche Scientifique, UMR 7275, 06560 Valbonne,  France.
authors: Anne
authors: A
authors: Delaunay
authors: Xavier
authors: X
authors: Gasull
authors: Miguel
authors: M
authors: Salinas
authors: Jacques
authors: J
authors: Noël
authors: Valérie
authors: V
authors: Friend
authors: Eric
authors: E
authors: Lingueglia
authors: Emmanuel
authors: E
authors: Deval
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D045604:Extracellular Fluid / Q000737:chemistry*; D005453:Fluorescence; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D015222:Sodium Channels