title: Two di-leucine motifs regulate trafficking and function of mouse ASIC2a.
abstract: BACKGROUND
  Acid-sensing ion channels (ASICs) are proton-gated cation channels that mediate acid-induced responses in neurons. ASICs are important for mechanosensation, learning and memory, fear, pain, and neuronal injury. ASIC2a is widely expressed in the nervous system and modulates ASIC channel trafficking and activity in both central and peripheral systems. Here, to better understand mechanisms regulating ASIC2a, we searched for potential protein motifs that regulate ASIC2a trafficking.
  
  
  CONCLUSIONS
  We identified a LLDLL sequence in the C-terminal juxtamembrane region of ASIC2a. Deleting or mutating the LLDLL sequence increased total expression and surface levels of ASIC2a in CHO cells. Mutating either of the two LL motifs had a similar effect. We further assessed ASIC2a localization in organotypic hippocampal slice neurons. The LL motif mutants exhibited increased dendritic trafficking and elevated targeting to dendritic spines. Consistent with an efficient trafficking, the LL motif mutants increased acid-activated current density. In addition, mutating the second LL motif increased pH sensitivity of the channel. These data identify the LL motifs as a negative regulator of ASIC2a trafficking and function, and suggest novel regulatory mechanisms in acid signaling.
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. wu@southalabama.edu.|China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai, 201203, China. wu@southalabama.edu.
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Neurobiology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, 30310, GA, USA. tleng@msm.edu.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Leng
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. ljing_a@yahoo.com.|State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Rd, Shanghai, 200040, China. ljing_a@yahoo.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. nanjiang126@126.com.|Shanghai University School of Life Sciences, Shanghai, China. nanjiang126@126.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai, 201203, China. hccb001@163.com.
authors.forename: Daijie
authors.initials: D
authors.lastname: Chen
authors.affiliation: China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai, 201203, China. bebydou@hotmail.com.
authors.forename: Youjia
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurobiology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, 30310, GA, USA. zxiong@msm.edu.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama College of Medicine, 5851 USA Dr N, MSB3074, Mobile, AL, 36688, USA. zha@southalabama.edu.
authors.forename: Xiang-ming
authors.initials: XM
authors.lastname: Zha
mesh_terms: D062565:Acid Sensing Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003712:Dendrites / Q000378:metabolism; D006031:Glycosylation; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D021381:Protein Transport; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C568265:ASIC2 protein, mouse; D062565:Acid Sensing Ion Channels
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