TY - JOUR
T1 - 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
AU - Nakashima, Yasunori M.
AU - Todorovic, Slobodan M.
AU - Covey, Douglas F.
AU - Lingle, Christopher J.
PY - 1998/9
Y1 - 1998/9
N2 - High voltage-activated (HVA) Ca2+ current (I(Ca)) 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 I((CA)). 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.
AB - High voltage-activated (HVA) Ca2+ current (I(Ca)) 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 I((CA)). 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.
UR - http://www.scopus.com/inward/record.url?scp=0031595681&partnerID=8YFLogxK
U2 - 10.1124/mol.54.3.559
DO - 10.1124/mol.54.3.559
M3 - Article
C2 - 9730915
AN - SCOPUS:0031595681
SN - 0026-895X
VL - 54
SP - 559
EP - 568
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 3
ER -