The Signal Transduction Mechanism Of Neurosteroid Pregnenolone Sulfate On Presynaptic Glutamate Release In Rat Prelimbic Cortex

Pregnenolone sulfate (PREGS) is one of the most abundant and the most active members of neurosteroids in the brain. And it is possible to be a novel kind of neuromessenger responsible for acute modulation of neurotransmission. Evidence showed by using electrophysiology that PREGS could significantly increase presynaptic glutamate release in rat prelimbic cortex. Morover, we found that the mechanism of the effect of PREGS was via the activation of presynapticα₁-adrenergic receptor and metabotropicσ₁-like receptor. It was possible that protein kinase A (PKA) played a key role in the effect of PREGS. The present paper studied the effect and mechanism of PREGS on PKA using biochemical methods combined with a pharmacological approach. The results suggested that PREGS had a selective enhancing effect on PKA activity in the prlimbic cortex and the hippocampus but not in the striatum. The effect of PREGS in the prelimbic cortex appeared to be via modulation of presynapticα₁-adrenergic receptors andσ₁ receptors, but in the hippocampus it might be dependent onσ₁ receptors only. The activation ofα₁-adrenergic receptors synergizedσ₁ receptors activation in the prelimbic cortex. In our further study we investigated the influence of other intracellular signal transduction molecular: such as intracellular calcium released from calcium store, protein kinase C (PKC) and adenylyl cyclase (AC). The results indicated that all these molecular could block the effect of PREGS, which suggested that intracellular calcium, protein kinase C and adenylyl cyclase might be upstream events in the activation of protein kinase A after PREGS. The present paper also studied the effect and mechanism of PREGS on PKC and intracellular calcium using biochemical methods. The results suggested that PREGS had an enhancing effect on the activity of classical/conventional subtype of PKC and [Ca²⁺]_i in the prlimbic cortex. We test the effect of another analogy Dehydroepiandrosterone sulfate (DHEAS) which is also a sulphide of neurosteoids in order to study the universality of the effect of PREGS among neurosteroids, DHEAS which is the most abundant steroid in the plasma of youth and an important neurosteroid in the brain could also enhance the activity of PKA in both prelimbic cortex and hippocampus. However, the results indicate that the effect of DHEAS is not produced by the activation of the same receptors and the same signal transduction way as PREGS. In our further study, the results indicated that the effect of DHEAS in the prelimbic cortex appeared to be via modulation of presynaptic D₁ receptors andσ₁ receptors which could synergize D1 receptors. And then they could activate PKA to increase the presynaptic glutamate release. All our study showed that although some neurosteroids have the same effects, they have the different mechanism.