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

Subunit Inhibits Neurosteroid Modulation of GABA_A 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 GABA_A receptors has been observed with all subunit combinations investigated; however, hetero-oligomeric GABA_A receptors containing  subunits were not studied previously. We describe the effect of  subunit expression on 3,21-dihydroxy-5-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 1, 6, 3, and 2 subunit cDNAs, whereas cotransfection of  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  subunit cotransfection. These results suggest that the presence of the  subunit inhibits GABA_A receptor modulation but not the direct activation by neurosteroids. Cotransfection with  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  subunit mRNAs as compared with 4 DIV granule cells. The presence of  subunit mRNAs detected in individual cells correlated well with the lack of sensitivity to THDOC. These results suggest that developmental expression of GABA_A receptor  subunits may play an important role in determining the region-specific neurosteroid-induced modification of fast inhibitory synaptic function.

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

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