@article {Nakashima559, author = {Yasunori M. Nakashima and Slobodan M. Todorovic and Douglas F. Covey and Christopher J. Lingle}, title = {The Anesthetic Steroid (+)-3α-Hydroxy-5α-androstane-17β-carbonitrile Blocks N-, Q-, and R-Type, but Not L- and P-Type, High Voltage-Activated Ca2+ Current in Hippocampal and Dorsal Root Ganglion Neurons of the Rat}, volume = {54}, number = {3}, pages = {559--568}, year = {1998}, doi = {10.1124/mol.54.3.559}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {High voltage-activated (HVA) Ca2+ current (ICa) was recorded from neonatal rat hippocampal and adult rat dorsal root ganglion neurons. In both cell types, (+)-3α-hydroxy-5α-androstane-17β-carbonitrile [(+)-ACN], a neuroactive steroid, had no effect on nifedipine- (L-type) or ω-agatoxin IVA- (P-type) sensitive ICa. Selective blockade of N-type current with ω-conotoxin GVIA and of Q-type current with ω-conotoxin MVIIC indicated that (+)-ACN inhibits both N- and Q-type current components in both cell types. Current persisting after blockade of all other current components (R-type) was also sensitive to (+)-ACN. Half-blockade of (+)-ACN-sensitive HVA current occurred in the range of 3{\textendash}25 μm, with N-type current somewhat more sensitive than Q- or R-type. The (+)-ACN enantiomer, (-)-ACN, and pregnanolone were somewhat less effective at inhibiting total HVA current than (+)-ACN, whereas several steroid analogs, including alfaxalone, were relatively ineffective at inhibiting total HVA current. Neither guanosine-5'-O-(2-thio)diphosphate nor guanosine-5'-O-(3-thio)triphosphate altered the ability of (+)-ACN to inhibit HVA current in dorsal root ganglion neurons, indicating that (+)-ACN acts directly on Ca2+channels. The partial selectivity exhibited by (+)-ACN among different HVA current components suggests that manipulations of steroid analogues may be a useful strategy in the generation of more selective, more potent, small-molecular-weight HVA channel blockers.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/54/3/559}, eprint = {https://molpharm.aspetjournals.org/content/54/3/559.full.pdf}, journal = {Molecular Pharmacology} }