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The Journal of Neuroscience, February 15, 2001, 21(4):1127-1136
Structural Determinants of Fast Desensitization and
Desensitization-Deactivation Coupling in GABAA
Receptors
Matt T.
Bianchi1,
Kevin
F.
Haas1, and
Robert L.
Macdonald2, 3
1 Neuroscience Graduate Program and the Departments of
2 Neurology and 3 Physiology, University of
Michigan, Ann Arbor, Michigan 48104-1687
Fast IPSCs in the brain are predominantly caused by
presynaptic release of GABA that activates GABAA
receptor (GABAAR) channels. The IPSCs are shaped by the
gating and desensitization properties of postsynaptic
GABAARs. Specifically, fast desensitization has been
suggested to decrease IPSC amplitude and to increase IPSC duration by
slowing deactivation; however, the mechanisms underlying desensitization, deactivation, and their coupling are poorly
understood. Consistent with this suggestion,  1 3 2L
GABAARs desensitize with a prominent fast phase and
deactivate slowly, whereas 13 GABAARs desensitize
without a fast phase and deactivate rapidly. Using the
concentration-jump technique applied to excised patches, we studied
GABAARs containing chimeras or exchange mutants between and 2L subunits to gain insight into the structural bases for fast
desensitization and its coupling to deactivation. We demonstrated that
the N terminus and two adjacent residues (V233, Y234) in the first
transmembrane domain (TM1) of the subunit were both required to
abolish fast desensitization. Additionally, these residues in TM1 of
the 2L subunit (Y235, F236) were critical for desensitized states to
prolong deactivation after removal of GABA, because mutations resulted
in accelerated deactivation despite unaltered desensitization time
course. Interestingly, control of desensitization and deactivation was
independent of the identity (2L or subunit sequence) of TM2,
indicating that structures related to the putative channel gate may
play a less direct role in desensitization than previously suggested.
Key words:
GABAA receptor; desensitization; deactivation; rapid kinetics; concentration-jump; recombinant
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141127-10$05.00/0
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