serval:BIB_A6BFB1AFAE84
Extracellular Subunit Interactions Control Transitions between Functional States of Acid-sensing Ion Channel 1a.
10.1074/jbc.M115.641688
000358511700029
26070563
Gwiazda
K.
author
Bonifacio
G.
author
Vullo
S.
author
Kellenberger
S.
author
article
2015
Journal of Biological Chemistry
1083-351X
0021-9258
journal
290
29
17956-17966
Acid-sensing ion channels (ASICs) are neuronal, voltage-independent Na(+) channels that are transiently activated by extracellular acidification. They are involved in pain sensation, the expression of fear, and in neurodegeneration after ischemic stroke. Our study investigates the role of extracellular subunit interactions in ASIC1a function. We identified two regions involved in critical intersubunit interactions. First, formation of an engineered disulfide bond between the palm and thumb domains leads to partial channel closure. Second, linking Glu-235 of a finger loop to either one of two different residues of the knuckle of a neighboring subunit opens the channel at physiological pH or disrupts its activity. This suggests that one finger-knuckle disulfide bond (E235C/K393C) sets the channel in an open state, whereas the other (E235C/Y389C) switches the channel to a non-conducting state. Voltage-clamp fluorometry experiments indicate that both the finger loop and the knuckle move away from the β-ball residue Trp-233 during acidification and subsequent desensitization. Together, these observations reveal that ASIC1a opening is accompanied by a distance increase between adjacent thumb and palm domains as well as a movement of Glu-235 relative to the knuckle helix. Our study identifies subunit interactions in the extracellular loop and shows that dynamic changes of these interactions are critical for normal ASIC function.
ASIC
subunit interaction
disulfide bond
protein-protein interaction
gating
electrophysiology
hydrogen bond
voltage-clamp fluorometry
eng
60_published
true
peer-reviewed
Publication types: Journal ArticlePublication Status: ppublish
University of Lausanne
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