PT  - JOURNAL ARTICLE
AU  - Conor Smith
AU  - Stella C Martin
AU  - Kavitha Sugunan
AU  - Shelley J Russek
AU  - Terrell T Gibbs
AU  - David H Farb
TI  - A Role for Picomolar Concentrations of Pregnenolone Sulfate in Synaptic Activity-dependent Ca<sup>2+</sup> signaling and CREB Activation
AID  - 10.1124/mol.114.094128
DP  - 2014 Jul 23
TA  - Molecular Pharmacology
PG  - mol.114.094128
4099  - http://molpharm.aspetjournals.org/content/early/2014/07/23/mol.114.094128.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/07/23/mol.114.094128.full
AB  - Fast excitatory synaptic transmission that is contingent upon N-methyl D-aspartate (NMDA) receptor function contributes to core information flow in the central nervous system (CNS) and to the plasticity of neural circuits that underlie cognition. Hypoactivity of excitatory NMDA receptor-mediated neurotransmission is hypothesized to underlie the pathophysiology of schizophrenia, including the associated cognitive deficits. The neurosteroid pregnenolone (PREG) and its metabolites pregnenolone sulfate (PregS) and allopregnanolone in serum are inversely associated with cognitive improvements following oral PREG therapy, raising the possibility that brain neurosteroid levels may be modulated therapeutically. PregS is derived from pregnenolone (PREG), the precursor of all neurosteroids, via a single sulfation step and is present at low nanomolar concentrations in the CNS. PregS, but not PREG, augments LTP and cognitive performance in animal models of learning and memory. In this report, we communicate the first observation that PregS, but not PREG, is a potent (EC50 ~ 2pM) enhancer of intracellular Ca2+ that is contingent upon neuronal activity, NMDAR-mediated synaptic activity, and L-type Ca2+ channel activity. Low pM PregS similarly activates CREB, an essential memory molecule, via an ERK/MAPK signal transduction pathway. Taken together, the results are consistent with a novel biological role for the neurosteroid PregS that acts at picomolar concentrations to intensify the intracellular response to glutamatergic signaling at synaptic, but not extra-synaptic, NMDA receptors by differentially augmenting CREB activation. This provides a genomic signal transduction mechanism by which PregS could participate in memory consolidation of relevance to cognitive function.