Abstract:
:Structure-function studies of the Cys loop family of ionotropic neurotransmitter receptors (GABA, nACh, 5-HT(3), and glycine receptors) have resulted in a six-loop (A-F) model of the agonist-binding site. Key amino acids have been identified in these loops that associate with, and stabilize, bound ligand. The next step is to identify the structural rearrangements that couple agonist binding to channel opening. Loop F has been proposed to move upon receptor activation, although it is not known whether this movement is along the conformational pathway for channel opening. We test this hypothesis in the GABA receptor using simultaneous electrophysiology and site-directed fluorescence spectroscopy. The latter method reveals structural rearrangements by reporting changes in hydrophobicity around an environmentally sensitive fluorophore attached to defined positions of loop F. Using a series of ligands that span the range from full activation to full antagonism, we show there is no correlation between the rearrangements in loop F and channel opening. Based on these data and agonist docking simulations into a structural model of the GABA binding site, we propose that loop F is not along the pathway for channel opening, but rather is a component of the structural machinery that locks ligand into the agonist-binding site.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Khatri A,Sedelnikova A,Weiss DSdoi
10.1016/j.bpj.2008.09.011subject
Has Abstractpub_date
2009-01-01 00:00:00pages
45-55issue
1eissn
0006-3495issn
1542-0086pii
S0006-3495(08)00020-9journal_volume
96pub_type
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