Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors.
Dehydroepiandrosterone sulphate is one of the most important neurosteroids. In the present paper, we studied the effect of dehydroepiandrosterone sulphate on persistent sodium currents and its mechanism and functional consequence with whole-cell patch clamp recording method combined with a pharmacological approach in the rat medial prefrontal cortex slices. The results showed that dehydroepiandrosterone sulphate inhibited the amplitude of persistent sodium currents and the inhibitory effect was significant at 0.1 microM, reached maximum at 1 microM and decreased with the increase in the concentrations of above 1 microM. The effect of dehydroepiandrosterone sulphate on persistent sodium currents was canceled by the Gi protein inhibitor and the protein kinase C inhibitor, but not by the protein kinase A inhibitor. The effect of dehydroepiandrosterone sulphate on persistent sodium currents was also canceled by the sigma-1 receptor blockers and the sigma-1 receptor agonist could mimic the effect of dehydroepiandrosterone sulphate. Dehydroepiandrosterone sulphate had no significant influence on neuronal excitability but could significantly inhibit chemical inhibition of mitochondria-evoked increase in persistent sodium currents. These results suggest that dehydroepiandrosterone sulphate inhibits persistent sodium currents via the activation of sigma-1 receptors-Gi protein-protein kinase C-coupled signaling pathway, and the main functional consequence of this effect of DHEAS is presumably to protect neurons under ischemia.
State Key Laboratory of Medical Neurobiology, Fudan University Shanghai Medical College, Institutes of Brain Science of Fudan University, Shanghai, PR China.
Zheng-Xiang
ZX
Cheng
Dan-Mei
DM
Lan
Pei-Ying
PY
Wu
Yan-Hua
YH
Zhu
Yi
Y
Dong
Lan
L
Ma
Ping
P
Zheng
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010648:Phenylacetates / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D000097605:Sigma-1 Receptor
D019314:Dehydroepiandrosterone Sulfate; D004791:Enzyme Inhibitors; D010648:Phenylacetates; D011759:Pyrrolidines; D017480:Receptors, sigma; D015222:Sodium Channels; D000097605:Sigma-1 Receptor; C404214:AC 915