Functional Assessment of the Calcium Messenger System in Cultured Mouse Leydig Tumor Cells: Regulation of Human Chorionic Gonadotropin-Induced Expression of the Steroidogenic Acute Regulatory Protein

Manna, Pulak R.

doi:10.1210/en.140.4.1739

Cited by 44 publications

(34 citation statements)

References 45 publications

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“…As previously suggested by others, store-operated Ca 2+ influx is one possibility [12,13]. The other possibility is that surface density or Ca +2 channel membrane activity is subjected to hCG signalling pathway effector proteins [28], possibly through phosphorylation, membrane trafficking or both. In fact, evidence has accumulated in favour of the involvement of protein phosphorylation, which facilitates Leydig cell steroidogenesis [35].…”

Section: Discussionmentioning

confidence: 78%

“…Two different stimulation protocols have routinely induced steroidogenesis in Leydig cells: tropic hormonal stimulation with LH/hCG and direct treatment with cAMP-a downstream second messenger-or an analogue [3,31]. In the present study, hCG receptor stimulation was preferred (i) to preserve Ca 2+ -mediated signalling activated by hCG and (ii) because a functional correlation between an hCG-induced increase in [Ca 2+ ] i and StAR expression has been well documented in Leydig cells [28,32]. Therefore, our current working hypothesis is that the binding of LH/hCG to its specific receptors on the Leydig cell membranes is followed by a sequence of intracellular events that lead to an increase in [Ca 2+ ] i that is responsible, at least in part, for StAR expression (possibly through transcription factor-mediated gene expression regulation effects).…”

Section: Discussionmentioning

confidence: 95%

“…The rate-limiting step in steroid biosynthesis is the transport of cholesterol to the inner mitochondrial membrane, a process that is dependent on the actions of StAR [28,29,31]. Two different stimulation protocols have routinely induced steroidogenesis in Leydig cells: tropic hormonal stimulation with LH/hCG and direct treatment with cAMP-a downstream second messenger-or an analogue [3,31].…”

Section: Discussionmentioning

confidence: 99%

“…For example, when the primary culture of rodent Leydig cells was incubated with Ni 2+ , nifedipine, or nimodipine, decreases in LH-induced and lactate-stimulated testosterone production might result from a blockade of VDCC type Ca 2+ channels [24,27]. In addition, the inhibitory actions of putative L-type Ca 2+ channel blockers on hCG-or cAMP-stimulated steroidogenesis are mediated by transcriptional repression of the StAR gene in mouse Leydig tumour cells [28,34]. Collectively, these results clearly suggest that Ca 2+ entry is needed for steroidogenesis in Leydig cells.…”

Section: Discussionmentioning

confidence: 99%

“…The hCG-stimulated expression of StAR mRNA, a key regulator of steroid biosynthesis, has been closely correlated with steroidogenesis in Leydig cells [28,29]. Consistently, our RT-PCR analysis revealed that Leydig cell stimulation with hCG at 100 IU gave rise to StAR mRNA expression detectable by RT-PCR and that mibefradil diminished hCG-stimulated StAR mRNA expression in a dose-dependent manner with a significant decrease seen at 1 mmol L −1 (P < 0.05; Figure 3A and 3B).…”

Section: Hcg-stimulated Star Mrna Expression Is Inhibited By Mibefradilmentioning

confidence: 99%

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Inhibitory actions of mibefradil on steroidogenesis in mouse Leydig cells: involvement of Ca2+ entry via the T-type Ca2+ channel

Lee¹,

Kim²,

Kim³

et al. 2010

Asian J Androl

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Intracellular cAMP and Ca 2+ are involved in the regulation of steroidogenic activity in Leydig cells, which coordinate responses to luteinizing hormone (LH) and human chorionic gonadotropin (hCG). However, the identification of Ca 2+ entry implicated in Leydig cell steroidogenesis is not well defined. The objective of this study was to identify the type of Ca 2+ channel that affects Leydig cell steroidogenesis. In vitro steroidogenesis in the freshly dissociated Leydig cells of mice was induced by hCG incubation. The effects of mibefradil (a putative T-type Ca 2+ channel blocker) on steroidogenesis were assessed using reverse transcription (RT)-polymerase chain reaction analysis for the steroidogenic acute regulatory protein (StAR) mRNA expression and testosterone production using radioimmunoassay. In the presence of 1.0 mmol L −1 extracellular Ca 2+ , hCG at 1 to 100 IU noticeably elevated both StAR mRNA level and testosterone secretion (P < 0.05), and the stimulatory effects of hCG were markedly diminished by mibefradil in a dose-dependent manner (P < 0.05). Moreover, the hCG-induced increase in testosterone production was completely removed when external Ca 2+ was omitted, implying that Ca 2+ entry is needed for hCG-induced steroidogenesis. Furthermore, a patch-clamp study revealed the presence of mibefradil-sensitive Ca 2+ currents seen at a concentration range that nearly paralleled those inhibiting steroidogenesis. Collectively, our data provide evidence that hCG-stimulated steroidogenesis is mediated at least in part by Ca 2+ entry carried out by the T-type Ca 2+ channel in the Leydig cells of mice.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hcg-stimulated Star Mrna Expression Is Inhibited By Mibefradilmentioning

confidence: 99%

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Inhibitory actions of mibefradil on steroidogenesis in mouse Leydig cells: involvement of Ca2+ entry via the T-type Ca2+ channel

Lee¹,

Kim²,

Kim³

et al. 2010

Asian J Androl

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Effects of L- and T-type Ca2+ channel blockers on spermatogenesis and steroidogenesis in the prepubertal mouse testis

Lee

Ahn

Lee

et al. 2010

J Assist Reprod Genet

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Purpose To assess the involvement of L-type and T-type Ca 2+ channel blockers in inducing male infertility. Methods Prepubertal male mice were fed Ca 2+ channel blockers nifedipine and ethosuximide for 20 days at dosages below maximum tolerated dose (MTD) and assayed for gross morphological changes in the testis such as body weight, testis size and weight. Sperm and Leydig cell counting were conducted concomitantly with serum testosterone level measurement by radioimmunoassay (RIA) and StAR protein mRNA measurement by reverse transcription and polymerase chain reaction (RT-PCR). Results A chronic exposure to nifedipine or ethosuximide caused a significant reduction in body weight, testis size/ weight and sperm production in a dose-dependent fashion associated with a spermatogenic arrest largely at the elongating spermatid stage. The number of Leydig cells, the serum testosterone level but not the luteinizing hormone level, and the content of StAR protein mRNA were also drastically reduced relative to the controls. Conclusions Both T-and L-type Ca 2+ channel blockers play an adverse role in normal spermatogenesis and steroidogenesis partly by blocking postmeiotic germ cell maturation and/or by abrogating StAR protein expression, contributing to male sterility. Therefore, any therapeutic application of Ca 2+ channel blockers must be used with caution due to its potential adverse side effects on male infertility.

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Role of the steroidogenic acute regulatory protein in health and disease

et al. 2015

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Steroid hormones are an important class of regulatory molecules that are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, brain and skin, and influence a spectrum of developmental and physiological processes. The steroidogenic acute regulatory protein (STAR) predominantly mediates the rate-limiting step in steroid biosynthesis, i.e., the transport of the substrate of all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane. At the inner membrane, cytochrome P450 cholesterol side chain cleavage enzyme cleaves the cholesterol side-chain to form the first steroid, pregnenolone, which is converted by a series of enzymes to various steroid hormones in specific tissues. Both basic and clinical evidence have demonstrated the crucial involvement of the STAR protein in the regulation of steroid biosynthesis. Multiple levels of regulation impinge on STAR action. Recent findings demonstrate that hormone-sensitive lipase, through its action on the hydrolysis of cholesteryl esters, plays an important role in regulating StAR expression and steroidogenesis which involve the liver X receptor pathway. Activation of the latter influences macrophage cholesterol efflux that is a key process in the prevention of atherosclerotic cardiovascular disease. Appropriate regulation of steroid hormones is vital for proper functioning of many important biological activities, which are also paramount for geriatric populations to live longer and healthier. This review summarizes the current level of understanding on tissue-specific and hormone-induced regulation of STAR expression and steroidogenesis, and provides insights into a number of cholesterol and/or steroid coupled physiological and pathophysiological consequences.

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Functional Assessment of the Calcium Messenger System in Cultured Mouse Leydig Tumor Cells: Regulation of Human Chorionic Gonadotropin-Induced Expression of the Steroidogenic Acute Regulatory Protein

Cited by 44 publications

References 45 publications

Inhibitory actions of mibefradil on steroidogenesis in mouse Leydig cells: involvement of Ca2+ entry via the T-type Ca2+ channel

Inhibitory actions of mibefradil on steroidogenesis in mouse Leydig cells: involvement of Ca2+ entry via the T-type Ca2+ channel

Effects of L- and T-type Ca2+ channel blockers on spermatogenesis and steroidogenesis in the prepubertal mouse testis

Role of the steroidogenic acute regulatory protein in health and disease

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