GABA synthesis in Schwann cells is induced by the neuroactive steroid allopregnanolone.
Recent evidence showed that neurotransmitters are synthesised in glial cells, such as the Schwann cells, which form myelin sheaths in the PNS. While the presence of GABA type A (GABA-A) receptors has been previously demonstrated in these cells, the evidence of GABA synthesis remained still elusive. In an attempt to demonstrate the presence of GABA in rat Schwann cells, we adopted a strategy, using several integrated neurochemical, molecular as well as immunocytochemical approaches. We first demonstrated the presence of glutamic acid decarboxylase of 67 kDa (GAD67) in Schwann cells, a crucial enzyme of the GABA synthesis mechanism. Second, we demonstrated that GABA is synthesized and localized in Schwann cells. As the third step we showed that allopregnanolone (10 nM), a potent allosteric modulator of GABA-A receptors, stimulates GABA synthesis through increased levels of GAD67 in Schwann cells. Analysis of intracellular signalling mechanisms revealed that the protein kinase A pathway, through enhanced cAMP levels and cAMP response element binding protein phosphorylation, modulates the allosteric action of allopregnanolone at the GABA-A receptor in Schwann cells. Our findings are the first to demonstrate that this GABA mechanism is active in Schwann cells thus establishing new potential therapeutic targets to control Schwann cell biology, which may prove useful in the treatment of several neurodegenerative disorders.
Magnaghi
Valerio
V
Department of Endocrinology, Physiopathology and Applied Biology, Università degli Studi di Milano, Milan, Italy.
Parducz
Arpad
A
Frasca
Angelisa
A
Ballabio
Marinella
M
Procacci
Patrizia
P
Racagni
Giorgio
G
Bonanno
Giambattista
G
Fumagalli
Fabio
F
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005576:Colforsin / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011280:Pregnanolone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000777:Anesthetics; D012333:RNA, Messenger; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2