Pregnenolone sulfate increases intracellular Ca2+ levels in a pituitary cell line

doi:10.1016/0014-2999(95)00772-5

European Journal of Pharmacology

Volume 298, Issue 1, 29 February 1996, Pages 79-85

https://doi.org/10.1016/0014-2999(95)00772-5 Get rights and content

Abstract

We have investigated the rapid steroid effects on intracellular calcium ([Ca²⁺]_i levels in a clonal pituitary cell line (GH3). Among the steroids tested only pregnenolone sulfate induced a rapid and transient [Ca²⁺]_i increase within 1 min. The specificity of pregnenolone sulfate-induced [Ca²⁺]_i increase with respect to steroid structure was pronounced. Other steroids (5–40 μM) including pregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, progesterone, estradiol-17β, testosterone, 5α-dihydrotestosterone, 5α-dihydroprogesterone, and 3α,5α-tetrahydroprogesterone were found to be ineffective. The [Ca²⁺]_i increase with pregnenolone sulfate (30 μM) was completely abolished in a Ca²⁺-free medium or in the presence of La³⁺ (0.1 mM) and Co²⁺ (5 mM). The organic Ca²⁺ channel blockers methoxyverapamil (100 μM) and nicardipine (5 μM) both showed similar inhibitions (> 73%). The interaction between pregnenolone sulfate and voltage-gated Ca²⁺ channels (VGCC) was shown by coapplication of pregnenolone sulfate (10 μM) with Bay K 8644 (0.1 mM) or KCl (15 mM). Coapplication of pregnenolone sulfate with KCl increased the [Ca²⁺]_i in an additive manner. However, with the specific agonist Bay K 8644(±), the pregnenolone sulfate effect was potentiated in a majority of the cells, suggesting cooperative interaction between the two. The results demonstrate that pregnenolone sulfate induces a rapid Ca²⁺ influx in GH3 cells. The marked nicardipine block also suggests that most of the Ca²⁺ influx is mediated through L-type VGCC.

References (43)

P.R. Albert et al.
Relationship of thyrotropin releasing hormone-induced spike and plateau phase in cytosolic free [Ca²⁺] concentrations to hormone secretion
J. Biol. Chem.
(1984)
E.E. Baulieu et al.
Neurosteroids: a new brain function
J. Steroid Biochem. Mol. Biol.
(1990)
P.F. Blackmore et al.
Progesterone and 17α-hydroxyprogesterone
Novel stimulators of calcium influx in human sperm
J. Biol. Chem.
(1990)
D.E. Dluzen et al.
Intermittent infusion of progesterone potentiates whereas continuous infusion reduces amphetamine-stimulated dopamine release from ovariectomized estrogen-primed rat striated fragments superfused in vitro
Brain Res.
(1987)
E.F. Etter et al.
Detection of changes in near-membrane Ca²⁺ concentration using a novel membrane-associated Ca²⁺ indicator
J. Biol. Chem.
(1994)
R.P. Irwin et al.
Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular [Ca²⁺] in cultured rat hippocampal neurons
Neurosci. Lett.
(1992)
S. Kojima et al.
Serum steroid levels in children at birth and in early neonatal period
Am. J. Obstet. Gynecol.
(1981)
A. Lanthier et al.
Sex steroids and 5-en-5β-hydroxysteroids in specific regions of the human brain and cranial nerves
J. Steroid Biochem.
(1986)
M.D. Majewska
Neurosteroids: endogenous bimodal modulators of the GABA_A receptor
Mechanism of action and physiological significance
Prog. Neurobiol.
(1992)
D.A. Williams et al.
Intracellular calibration of the fluorescent calcium indicator Fura-2
Cell Calcium
(1990)

T. Aizawa et al.

Differential effects of thyrotropin-releasing hormone, vasoactive intestinal peptide, phorbol ester and depolarization in GH₄C₁ rat pituitary cells

Endocrinology

(1985)

C.M. Armstrong et al.

Two distinct populations of calcium channels in a clonal line of pituitary cell

Science

(1985)

M.R. Bowlby

Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons

Mol. Pharmacol.

(1993)

C. Bukusoglu et al.

Analgesia with anesthetic steroids and ethanol

Anesth. Analg.

(1993)

R.J. Chang et al.

Simultaneous comparison of Δ⁵-3β-hydroxysteroid levels in the fetoplacental circulation of normal pregnancy in labor and not in labor

J. Clin. Endorinol. Metab.

(1976)

E. DePeretti et al.

Pattern of plasma pregnenolone sulfate levels in humans from birth to adulthood

J. Clin. Endocrinol. Metab.

(1983)

S.V. Drouva et al.

Effects of 17β-estradiol on LH-RH release from rat mediobasal hypothalmic slices

Neuroendocrinology

(1984)

S.V. Drouva et al.

Progesterone-induced LH-RH release in vitro is an estrogen as well as and calmodulin-dependent secretory process

Neuroendocrinology

(1985)

B. Dufy et al.

Membrane effects of thyrotropin-releasing hormone and estrogen shown by intracellular recording from pituitary cells

Science

(1979)

J.J. Enyeart et al.

Interaction of dihydropryridine CA²⁺ agonist Bay K 8644 with normal and transformed pituitary cells

J. Am. Physiol.

(1986)

J.M.H. ffrench-Mullen et al.

Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism

J. Neurosci.

(1994)

Cited by (15)

Modulation of neurotransmitter systems by dehydroepiandrosterone and dehydroepiandrosterone sulfate: Mechanism of action and relevance to psychiatric disorders
2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Dehydroepiandrosterone (DHEA) is synthesized in the brain and several studies have shown that this steroid is a modulator of synaptic transmission. The effect of DHEA, and its sulfate ester DHEAS, on glutamate and GABA neurotransmission has been extensively studied but some effects on other neurotransmitter systems, such as dopamine, serotonin and nitric oxide, have also been reported. This review summarizes studies showing the effect of DHEA and DHEAS on neurotransmitter systems at different levels (metabolism, release, reuptake, receptor activation), as well as the activation of voltage-gated ion channels and calcium homeostasis, showing the variety of effects that these steroids exert on those systems, allowing the discussion of its mechanisms of action and its relevance to psychiatric disorders.
Modulation of glutamatergic transmission by sulfated steroids: Role in fetal alcohol spectrum disorder
2008, Brain Research Reviews
Citation Excerpt :
It was demonstrated that PREGS modulates several ionotropic neurotransmitter receptors, including NMDA, AMPA, kainate, and glycine receptors (Gibbs et al., 2006). Metabotropic receptors, such as σ1 receptors and adrenergic receptors, as well as voltage-gated Ca2+ and K+ channels, have also been identified as targets of PREGS (Bukusoglu and Sarlak, 1996; Dong et al., 2005; Ffrench-Mullen et al., 1994; Hige et al., 2006; Maurice, 2004; Monnet and Maurice, 2006; Morin-Surun et al., 1999; Rupprecht and Holsboer, 1999; Sabeti et al., 2007; Spence et al., 1991; Wang et al., 1998). One of the best characterized neuronal targets of PREGS is the NMDA subtype of glutamate ionotropic receptors (NMDAR).
It is well established that sulfated steroids regulate synaptic transmission by altering the function of postsynaptic neurotransmitter receptors. In recent years, evidence from several laboratories indicates that these agents also regulate glutamatergic synaptic transmission at the presynaptic level in an age-dependent manner. In developing neurons, pregnenolone sulfate (PREGS) increases the probability of glutamate release, as evidenced by an increase in the frequency of AMPA receptor-mediated miniature excitatory postsynaptic currents and a decrease in paired-pulse facilitation. In hippocampal slices from postnatal day 3–5 rats, this effect is mediated by an increase in Ca²⁺ levels in the axonal terminal that depends on presynaptic NMDA receptors. This is followed by delayed potentiation of postsynaptic AMPA receptor currents. Importantly, depolarization of postsynaptic neurons, inhibition of hydroxysteroid sulfatase activity and acute exposure to ethanol mimics the effect of exogenous PREGS application. This developmental form of synaptic plasticity cannot be observed in slices from rats older than postnatal day 6, when presynaptic NMDA receptors are no longer expressed in CA1 hippocampal region. Both in the CA1 hippocampal region and the dentate gyrus of more mature rats, PREGS, dehydroepiandrosterone sulfate and hydroxysteroid sulfatase inhibitors increase paired-pulse facilitation, without affecting basal glutamate release probability. This effect depends on activation of σ₁-like receptors and G_i/o and involves a target in the release machinery that is downstream of residual Ca²⁺. These presynaptic actions of sulfated steroids could play important roles in physiological processes ranging from synapse maturation to learning and memory, as well as pathophysiological conditions such as fetal alcohol spectrum disorder.
Neuroactive steroids modulate in vitro the Mg<sup>2+</sup>-dependent Ca<sup>2+</sup>-ATPase activity in cultured rat neurons
1998, General Pharmacology
- 1.
  The in vitro effect of neuroactive steroids on the Mg²⁺-dependent Ca²⁺-ATPase activity in neuronal membranes isolated from primary cell culture of rat cortex was examined.
- 2.
  A 1-hr treatment of neuronal cell culture with 17-β-estradiol (10 pM) and pregnenolone sulfate (1 μM) resulted in an increase in the enzyme activity of as much as 130% and 160%, respectively.
- 3.
  Neuroactive steroids moderately decreased the stimulation of the Mg²⁺-dependent Ca²⁺-ATPase activity by 72 nM calmodulin, by 20–30%.
- 4.
  The effects of hormones on the ATPase activity were irreversible after extensive washing of the membranes.
- 5.
  These results suggest that 17-β-estradiol and pregnenolone sulfate at physiological concentrations could participate in the regulation of neuronal calcium homeostasis at a membrane level.
Activation of adrenal steroidogenesis and an improvement of mood balance in postmenopausal females after spa treatment based on physical activity
2019, International Journal of Molecular Sciences
Calcium-engaged mechanisms of nongenomic action of neurosteroids
2017, Current Neuropharmacology
Sigma receptors [ σ Rs]: Biology in normal and diseased states
2016, Journal of Receptors and Signal Transduction

View all citing articles on Scopus

View full text

Pregnenolone sulfate increases intracellular Ca2+ levels in a pituitary cell line

Abstract

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

J. Biol. Chem.

Brain Res.

J. Biol. Chem.

Neurosci. Lett.

Am. J. Obstet. Gynecol.

J. Steroid Biochem.

Prog. Neurobiol.

Cell Calcium

Differential effects of thyrotropin-releasing hormone, vasoactive intestinal peptide, phorbol ester and depolarization in GH4C1 rat pituitary cells

Endocrinology

Two distinct populations of calcium channels in a clonal line of pituitary cell

Science

Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons

Mol. Pharmacol.

Analgesia with anesthetic steroids and ethanol

Anesth. Analg.

Simultaneous comparison of Δ5-3β-hydroxysteroid levels in the fetoplacental circulation of normal pregnancy in labor and not in labor

J. Clin. Endorinol. Metab.

Pattern of plasma pregnenolone sulfate levels in humans from birth to adulthood

J. Clin. Endocrinol. Metab.

Effects of 17β-estradiol on LH-RH release from rat mediobasal hypothalmic slices

Neuroendocrinology

Progesterone-induced LH-RH release in vitro is an estrogen as well as and calmodulin-dependent secretory process

Neuroendocrinology

Membrane effects of thyrotropin-releasing hormone and estrogen shown by intracellular recording from pituitary cells

Science

Interaction of dihydropryridine CA2+ agonist Bay K 8644 with normal and transformed pituitary cells

J. Am. Physiol.

Neurosteroids modulate calcium currents in hippocampal CA1 neurons via a pertussis toxin-sensitive G-protein-coupled mechanism

J. Neurosci.

Pregnenolone sulfate increases intracellular Ca²⁺ levels in a pituitary cell line

Differential effects of thyrotropin-releasing hormone, vasoactive intestinal peptide, phorbol ester and depolarization in GH₄C₁ rat pituitary cells

Simultaneous comparison of Δ⁵-3β-hydroxysteroid levels in the fetoplacental circulation of normal pregnancy in labor and not in labor

Interaction of dihydropryridine CA²⁺ agonist Bay K 8644 with normal and transformed pituitary cells