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Volume 16, Number 21, Issue of November 1, 1996 pp. 6648-6656
Copyright ©1996 Society for Neuroscience

delta Subunit Inhibits Neurosteroid Modulation of GABAA Receptors

Received June 26, 1996; revised July 31, 1996; accepted Aug. 9, 1996.

Wei Jian Zhu1, Jian Feng Wang1, Karl E. Krueger2, and Stefano Vicini1

Departments of 1 Physiology and Biophysics and 2 Cell Biology, Georgetown University Medical Center, Washington, D.C. 20007

Neurosteroid modulation of GABAA receptors has been observed with all subunit combinations investigated; however, hetero-oligomeric GABAA receptors containing delta  subunits were not studied previously. We describe the effect of delta  subunit expression on 3alpha ,21-dihydroxy-5alpha -pregnan-20-1 (THDOC)-induced potentiation of GABA-gated currents in transfected HEK 293 cells and in cerebellar granule cells in vitro. THDOC (100 nM) significantly potentiated GABA-gated currents in cells transfected with combinations of alpha 1, alpha 6, beta 3, and gamma 2 subunit cDNAs, whereas cotransfection of delta  subunit cDNA inhibited this potentiation. In contrast, the direct Cl- channel activation by THDOC at higher concentrations (1-10 µM) was not significantly dependent on delta  subunit cotransfection. These results suggest that the presence of the delta  subunit inhibits GABAA receptor modulation but not the direct activation by neurosteroids. Cotransfection with delta  subunit also affected the negative allosteric modulation by pregnenolone sulfate. THDOC potentiation of GABA-gated currents was greater in cerebellar granule cell cultures at 4 d in vitro (DIV) compared with those at 14 DIV. Single-cell reverse transcription-PCR analysis of the mRNAs expressed in cultured cerebellar granule cells shows that an increased number of granule cells at 14 DIV express delta  subunit mRNAs as compared with 4 DIV granule cells. The presence of delta  subunit mRNAs detected in individual cells correlated well with the lack of sensitivity to THDOC. These results suggest that developmental expression of GABAA receptor delta  subunits may play an important role in determining the region-specific neurosteroid-induced modification of fast inhibitory synaptic function.

Key words: gamma -aminobutyric acid; GABAA receptor subunit; patch clamp; allopregnenolone; single-cell RT-PCR; cDNA transfection




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