Structural elements for the generation of sustained currents by the acid pain sensor ASIC3.
ASIC3 is an acid-sensing ion channel expressed in sensory neurons, where it participates in acidic and inflammatory pain. In addition to the "classical" transient current, ASIC3 generates a sustained current essential for pain perception. Using chimeras between the ASIC3 and ASIC1a channels we show that the first transmembrane domain (TM1), combined with the N-terminal domain, is the key structural element generating the low pH (<6.5)-evoked sustained current. The TM1 domain also modulates the pH-dependent activation of the fast transient current thus contributing to a constitutive window current, another type of sustained current present near physiological pH. The C-terminal and the TM2 domains negatively regulate both types of sustained current, and the extracellular loop affects its kinetics. These data provide new information to aid understanding the mechanisms of the multifaceted pH gating of ASIC3. Together with the peak current, both components of the sustained current (window and sustained at pH <6.5) allow ASIC3 to adapt its behavior to a wide range of extracellular pH variations by generating transient and/or sustained responses that contribute to nociceptor excitability.
Institut de Pharmacologie Moléculaire et Cellulaire and the Institut de NeuroMédecine Moléculaire, CNRS/Université de Nice Sophia-Antipolis UMR6097, 660, route des Lucioles, Sophia-Antipolis, F-06560 Valbonne, France.
Miguel
M
Salinas
Michel
M
Lazdunski
Eric
E
Lingueglia
D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism*; D000818:Animals; D004594:Electrophysiology; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D008564:Membrane Potentials; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010957:Plasmids; D051381:Rats; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000143:Acids; D009419:Nerve Tissue Proteins; D015222:Sodium Channels