DOES NEUROSTEROID MODULATORY EFFICACY DEPEND ON GABA(A) RECEPTOR SUBUNIT COMPOSITION

The modulation of GABA activity by 3alpha-OH-DHP (allopregnanolone, 3a lpha-hydroxy-5alpha-pregnan-20-one) and PS (pregnenolone sulfate) has been studied in native GABA(A) receptors of rat cortical neurons in pr imary cultures and in structurally different recombinant GABA(A) recep tors expressed in the 293 human embryonic kidney cell line (HEK 293). In cortical neurons 3alpha-OH-DHP positively modulates GABA elicited C l- currents while PS at 10 muM negatively modulates (50% decrease) thi s GABA response, but at 10 nM PS positively modulates the GABA current (40% increase). Both neurosteroids are equally active on various type s of recombinant GABA(A) receptors, except for alph6beta1gamma2 recept ors which are less sensitive to the positive allosteric modulation by 3alpha-OH-DHP. In contrast the presence of the gamma1 subunit doubles the efficacy of 3alpha-OH-DHP. The negative modulation of PS is simila r in recombinant GABAA receptors including various molecular forms of a or gamma units. A direct activation of Cl- current by 3alpha-OH-DHP was observed in native and recombinant receptors but its efficacy on t he various molecular forms of GABA(A) receptor tested was always small er than that of identical concentrations (10 muM) of GABA.