Regulation of sensory neuron-specific acid-sensing ion channel 3 by the adaptor protein Na+/H+ exchanger regulatory factor-1.
Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. The ASIC3 subunit is largely expressed in the peripheral nervous system, where it contributes to pain perception and to some aspects of mechanosensation. We report here a PDZ-dependent and protein kinase C-modulated association between ASIC3 and the Na+/H+ exchanger regulatory factor-1 (NHERF-1) adaptor protein. We show that NHERF-1 and ASIC3 are co-expressed in dorsal root ganglion neurons. NHERF-1 enhances the ASIC3 peak current in heterologous cells, including F-11 dorsal root ganglion cells, by increasing the amount of channel at the plasma membrane. Perhaps more importantly, we show that the plateau current of ASIC3 can be dramatically increased (10-30-fold) by association with NHERF-1, leading to a significant sustained current at pH 6.6. In the presence of NHERF-1, the ASIC3 subcellular localization is modified, and the channel co-localizes with ezrin, a member of the ezrin-radixin-moesin family of actin-binding proteins, providing the first direct link between ASIC3 and the cortical cytoskeleton. Given the importance of the ASIC3 sustained current in nociceptor excitability, it is likely that NHERF-1 participates in channel functions associated with nociception and mechanosensation.
Deval
Emmanuel
E
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UNSA UMR 6097, Institut Paul Hamel, 660 Route des Lucioles, Sophia Antipolis, Valbonne 06560, France.
Friend
Valérie
V
Thirant
Cécile
C
Salinas
Miguel
M
Jodar
Martine
M
Lazdunski
Michel
M
Lingueglia
Eric
E
D062565:Acid Sensing Ion Channels; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D002522:Chlorocebus aethiops; D005727:Ganglia, Spinal / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D051381:Rats; D015222:Sodium Channels / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D015222:Sodium Channels; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor