Blockade of Ba2+ current through human α1E channels by two steroid analogs, (+)-ACN and (+)-ECN

Yasunori M. Nakashima, Alexei Pereverzev, Toni Schneider, Douglas F. Covey, Christopher J. Lingle

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Previous work suggests that different neuroactive steroids may exhibit some selectivity in their blocking effects on different high-voltage activated (HVA) Ca2+currents. At least some of these effects appear to involve direct blocking actions on Ca2+ channels. Thus, direct investigation of the effects of various steroids on cloned Ca2+ channel variants may lead to the development of potent and selective small-molecular weight Ca2+ channel blockers. Here we examine the effects of two steroids on a cloned human α1E Ca2+ channel both with and without a β3 subunit, when expressed in HEK293 cells. One compound, (+)-ACN, has been previously shown to block N-, Q-, and R-subtypes of HVA current without affecting L- and P-type current. The second compound, (+)-ECN, weakly blocks total HVA current in hippocampal neurons. (+)-ECN differs from (+)-ACN in lacking effects on GABA receptors, but shares with (+)-ACN an ability to partially inhibit T current in DRG neurons (Todorovic, S.M., Prakriya, M., Nakashima, Y.M. et al., 1998. Enantioselective blockade of T-type Ca2+ current in adult rat sensory neurons by a steroid lacking GABA-mimetic activity. Mol. Pharmacol. 54, 918-927). (+)-ACN can block 100% of Ba2+ current in HEK cells arising either from the α1E subunit (IC50~10 μM) or the α1Eβ3 combination (IC50~5 μM), while (+)-ECN maximally blocks only about 80% of the α1E (10 μM) or α1Eβ3 (16 μM) current. Blockade by (+)-ACN exhibits several differences from blockade by (+)-ECN. (+)-ACN increases the apparent rate of onset of inactivation, particularly for the α1E variant, slows recovery from inactivation, and more profoundly shifts the voltage-dependence of current availability for both α1E and α1Eβ3 variants than does (+)-ECN. Although the complexity of the normal inactivation kinetics of α1E variants makes interpretation of the (+)-ACN-induced kinetic alterations difficult, the results suggest that the two steroids are to some extent acting by distinct mechanisms, and perhaps at different sites. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)843-855
Number of pages13
Issue number6
StatePublished - Jun 15 1999


  • Anesthetics
  • Ca channels
  • Ca channels (α1E)
  • Ca currents (R-type)
  • Neuroactive steroids
  • Steroids


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