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Journal of Neuroscience, Vol 14, 1963-1977, Copyright © 1994 by Society for Neuroscience
Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism
JM ffrench-Mullen, P Danks and KT Spence
Department of Pharmacology, Zeneca Pharmaceuticals Group, Zeneca Inc., Wilmington, Delaware 19897.
The inhibition of Ca2+ channel currents by endogenous brain steroids was
examined in freshly dissociated pyramidal neurons from the adult guinea pig
hippocampal CA1 region. The steady-state inhibition of the peak Ca2+
channel current evoked by depolarizing steps from -80 to -10 mV occurred in
a concentration-dependent manner with the following IC50 values:
pregnenolone sulfate (PES), 11 nM; pregnenolone (PE), 130 nM; and
allotetrahydrocorticosterone (THCC), 298 nM. THCC, PE, and PES depressed a
fraction of the Ca2+ channel current with a maximal inhibition of 60% of
the total current. However, substitution of an acetate group for the
sulfate group on PES resulted in a complete loss of activity. Progesterone
had no effect (4% inhibition at 100 microM). Intracellular dialysis of PES
had no effect on the Ca2+ current; concomitant extracellular perfusion of
PES showed normal inhibitory activity, suggesting that the steroid binding
site can only be accessed extracellularly. Analysis of tail currents at -80
mV demonstrated that THCC and PES slowed the rate of Ca2+ current
activation and deactivation with no change in the voltage dependence of
activation. Inhibition of the Ca2+ channel current by THCC and PES was
voltage dependent. THCC primarily inhibits the omega-conotoxin
(CgTX)-sensitive or N-type Ca2+ channel current. PE was nonselective in
inhibiting both the CgTX- and the nifedipine (NIF)-sensitive Ca2+ channel
current. These neurosteroids had no effect on the CgTX/NIF-insensitive
current. In neurons isolated from pertussis toxin (PTX)-treated animals by
chronic intracerebroventricular infusion (1000 ng/24 hr for 48 hr), the
Ca2+ channel current inhibition by PES, PE, and THCC was significantly
diminished. Intracellular dialysis with GDP-beta-S (500 microM) also
significantly diminished the neurosteroid inhibition of the Ca2+ channel
current. Intracellular dialysis with the general kinase inhibitors H-7 (100
microM), staurosporine (400 nM), and a 20 amino acid protein kinase
inhibitor (1 microM) also significantly prevented the THCC and PES
inhibition of the Ca2+ channel current. Intracellular dialysis with the
more specific inhibitors of protein kinase C (PKC), the pseudosubstrate
inhibitor (PKCI 19-36) (1-2 microM) and bisindolylmaleimide (1 microM)
significantly diminished the THCC and PE inhibition of the Ca2+ channel
current. Rp- cAMP (100 microM), a specific inhibitor of cAMP-dependent
protein kinase (PKA), had no effect on the THCC and PE inhibition of the
Ca2+ current.(ABSTRACT TRUNCATED AT 400 WORDS)
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