The cytoskeletal protein alpha-actinin regulates acid-sensing ion channel 1a through a C-terminal interaction.
The acid-sensing ion channel 1a (ASIC1a) is widely expressed in central and peripheral neurons where it generates transient cation currents when extracellular pH falls. ASIC1a confers pH-dependent modulation on postsynaptic dendritic spines and has critical effects in neurological diseases associated with a reduced pH. However, knowledge of the proteins that interact with ASIC1a and influence its function is limited. Here, we show that alpha-actinin, which links membrane proteins to the actin cytoskeleton, associates with ASIC1a in brain and in cultured cells. The interaction depended on an alpha-actinin-binding site in the ASIC1a C terminus that was specific for ASIC1a versus other ASICs and for alpha-actinin-1 and -4. Co-expressing alpha-actinin-4 altered ASIC1a current density, pH sensitivity, desensitization rate, and recovery from desensitization. Moreover, reducing alpha-actinin expression altered acid-activated currents in hippocampal neurons. These findings suggest that alpha-actinins may link ASIC1a to a macromolecular complex in the postsynaptic membrane where it regulates ASIC1a activity.
Schnizler
Mikael K
MK
Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Schnizler
Katrin
K
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Zha
Xiang-Ming
XM
Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Hall
Duane D
DD
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Wemmie
John A
JA
Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242; Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242.
Hell
Johannes W
JW
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Welsh
Michael J
MJ
Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242; Departments of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242. Electronic address: michael-welsh@uiowa.edu.
D062565:Acid Sensing Ion Channels; D000185:Actinin / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*
C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D000185:Actinin