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Volume 17, Number 11,
Issue of June 1, 1997
pp. 4022-4031
Copyright ©1997 Society for Neuroscience
Neurosteroid Prolongs GABAA Channel Deactivation by
Altering Kinetics of Desensitized States
Received Jan. 9, 1997; revised March 5, 1997; accepted March 12, 1997.
Wei Jian Zhu and
Stefano Vicini
Department of Physiology and Biophysics, Georgetown University
School of Medicine, Washington, DC 20007
Fast applications of GABA (1 mM) to nucleated and
outside-out patches excised from granule neurons in cerebellar slices
from developing rats evoked currents with a double exponential time course reminiscent of that of IPSCs. A neurosteroid 3 ,
21dihydroxy-5-pregnan-20-one (THDOC) remarkably increased the
slow deactivation time constant and slowed down recovery from
desensitization, as estimated by paired-pulse GABA applications. THDOC
also reduced the amplitude of GABA currents, whereas it failed to
affect the fast deactivation component and its relative contribution to
peak amplitude. The effects of THDOC on slow deactivation were greater
in rats younger than postnatal day 13 (P13) as compared with rats at
P30-P35. THDOC failed to alter deactivation of short responses induced by a less-potent agonist taurine at saturating doses. These responses had deactivation kinetics described by a fast single exponential decay,
little desensitization, and quick recovery. However, THDOC slowed
deactivation if taurine responses were long enough to allow consistent
desensitization, suggesting that desensitized states are required for
the neurosteroid to modulate GABA responses. In outside-out patches,
just as desensitized states prolonged GABA responses by producing
reopening of channels activated by brief GABA pulses, THDOC increased
the channel open probability by further increasing the number of late
channel openings, resulting in a prolongation of the slow deactivation.
Our data suggest that neurosteroid potentiates the inhibitory
postsynaptic transmission via the prolongation of the slow deactivation
and that the alteration of kinetics of entry and exit from desensitized
states underlies the allosteric modification of GABAA
receptors by neurosteroids.
Key words:
GABAA receptor;
desensitization;
THDOC;
IPSC;
taurine;
patch clamp
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