Metabotropic, but not allosteric, effects of neurosteroids on GABAergic inhibition depend on the phosphorylation of GABA receptors.

Neuroactive steroids (NASs) are synthesized within the brain and exert profound effects on behavior. These effects are primarily believed to arise from the activities of NASs as positive allosteric modulators (PAMs) of the GABA-type A receptor (GABAR). NASs also activate a family of G protein-coupled receptors known as membrane progesterone receptors (mPRs).

Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C-dependent mechanism.

The neuroactive steroid (NAS) tetrahydrodeoxycorticosterone (THDOC) increases protein kinase C (PKC) mediated phosphorylation of extrasynaptic GABA receptor (GABAR) subunits leading to increased surface expression of α4/β3 subunit-containing extrasynaptic GABARs, leading to a sustained increase in GABAR tonic current density. Whether other naturally occurring and synthetic NASs share both an allosteric and metabotropic action on GABARs is unknown. Here, we examine the allosteric and metabotropic properties of allopregnanolone (ALLO), and synthetic NASs SGE-516 and ganaxolone.