TY - JOUR
T1 - Anticonvulsant and anesthetic effects of a fluorescent neurosteroid analog activated by visible light
AU - Eisenman, Lawrence N.
AU - Shu, Hong Jin
AU - Akk, Gustav
AU - Wang, Cunde
AU - Manion, Brad D.
AU - Kress, Geraldine J.
AU - Evers, Alex S.
AU - Steinbach, Joe Henry
AU - Covey, Douglas F.
AU - Zorumski, Charles F.
AU - Mennerick, Steven
N1 - Funding Information:
We thank A. Taylor, A. Benz and B.-W. Ma for technical help and laboratory members for advice and discussion. This work was supported by a gift from the Bantly Foundation (C.F.Z.) and by US National Institutes of Health grants
PY - 2007/4
Y1 - 2007/4
N2 - Most photoactivatable compounds suffer from the limitations of the ultraviolet wavelengths that are required for activation. We synthesized a neuroactive steroid analog with a fluorescent (7-nitro-2,1,3-benzoxadiazol-4-yl) amino (NBD) group in the β configuration at the C2 position of (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone, 3α5αP). Light wavelengths (480 nm) that excite compound fluorescence strongly potentiate GABAA receptor function. Potentiation is limited by photodepletion of the receptor-active species. Photopotentiation is long-lived and stereoselective and shows single-channel hallmarks similar to steroid potentiation. Other NBD-conjugated compounds also generate photopotentiation, albeit with lower potency. Thus, photopotentiation does not require a known ligand for neurosteroid potentiating sites on the GABA A receptor. Photoactivation of a membrane-impermeant, fluorescent steroid analog demonstrates that membrane localization is critical for activity. The photoactivatable steroid silences pathological spiking in cultured rat hippocampal neurons and anesthetizes tadpoles. Fluorescent steroids photoactivated by visible light may be useful for modulating GABAA receptor function in a spatiotemporally defined manner.
AB - Most photoactivatable compounds suffer from the limitations of the ultraviolet wavelengths that are required for activation. We synthesized a neuroactive steroid analog with a fluorescent (7-nitro-2,1,3-benzoxadiazol-4-yl) amino (NBD) group in the β configuration at the C2 position of (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone, 3α5αP). Light wavelengths (480 nm) that excite compound fluorescence strongly potentiate GABAA receptor function. Potentiation is limited by photodepletion of the receptor-active species. Photopotentiation is long-lived and stereoselective and shows single-channel hallmarks similar to steroid potentiation. Other NBD-conjugated compounds also generate photopotentiation, albeit with lower potency. Thus, photopotentiation does not require a known ligand for neurosteroid potentiating sites on the GABA A receptor. Photoactivation of a membrane-impermeant, fluorescent steroid analog demonstrates that membrane localization is critical for activity. The photoactivatable steroid silences pathological spiking in cultured rat hippocampal neurons and anesthetizes tadpoles. Fluorescent steroids photoactivated by visible light may be useful for modulating GABAA receptor function in a spatiotemporally defined manner.
UR - http://www.scopus.com/inward/record.url?scp=33947612643&partnerID=8YFLogxK
U2 - 10.1038/nn1862
DO - 10.1038/nn1862
M3 - Article
C2 - 17322875
AN - SCOPUS:33947612643
SN - 1097-6256
VL - 10
SP - 523
EP - 530
JO - Nature neuroscience
JF - Nature neuroscience
IS - 4
ER -