PT  - JOURNAL ARTICLE
AU  - Nakashima, Yasunori M.
AU  - Todorovic, Slobodan M.
AU  - Covey, Douglas F.
AU  - Lingle, Christopher J.
TI  - The Anesthetic Steroid (+)-3α-Hydroxy-5α-androstane-17β-carbonitrile Blocks N-, Q-, and R-Type, but Not <span class="sc">L</span>- and P-Type, High Voltage-Activated Ca<sup>2+</sup> Current in Hippocampal and Dorsal Root Ganglion Neurons of the Rat
AID  - 10.1124/mol.54.3.559
DP  - 1998 Sep 01
TA  - Molecular Pharmacology
PG  - 559--568
VI  - 54
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/54/3/559.short
4100  - http://molpharm.aspetjournals.org/content/54/3/559.full
SO  - Mol Pharmacol1998 Sep 01; 54
AB  - 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 3–25 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.