Abstract:
:Proper regulation of neurotransmission requires that ligand-activated ion channels remain closed until agonist binds. How channels then open remains poorly understood. Glycine receptor (GlyR) gating is initiated by agonist binding at interfaces between adjacent subunits in the extracellular domain. Aspartate-97, located at the alpha1 GlyR interface, is a conserved residue in the cys-loop receptor superfamily. The mutation of D97 to arginine (D97R) causes spontaneous channel opening, with open and closed dwell times similar to those of maximally activated WT GlyR. Using a model of the N-terminal domain of the alpha1 GlyR, we hypothesized that an arginine-119 residue was forming intersubunit electrostatic bonds with D97. The D97R/R119E charge reversal restored this interaction, stabilizing channels in their closed states. Cysteine substitution shows that this link occurs between adjacent subunits. This intersubunit electrostatic interaction among GlyR subunits thus contributes to the stabilization of the closed channel state, and its disruption represents a critical step in GlyR activation.
journal_name
Proc Natl Acad Sci U S Aauthors
Todorovic J,Welsh BT,Bertaccini EJ,Trudell JR,Mihic SJdoi
10.1073/pnas.1001845107subject
Has Abstractpub_date
2010-04-27 00:00:00pages
7987-92issue
17eissn
0027-8424issn
1091-6490pii
1001845107journal_volume
107pub_type
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