Elsevier

Cell Calcium

Volume 40, Issue 2, August 2006, Pages 155-164
Cell Calcium

T channels and steroid biosynthesis: in search of a link with mitochondria

https://doi.org/10.1016/j.ceca.2006.04.020Get rights and content

Abstract

The activity of T-type Ca2+ channels has been associated for a long time with steroid biosynthesis in adrenal cortical cells. Because Ca2+-dependent, rate-limiting steps of steroidogenesis have been shown to occur within the mitochondria, a functional link between these organelles and T-type channels has been thoroughly investigated. Based on several experimental data, a model has been proposed in which plasma-membrane-embedded T channels specifically bring calcium entering the cell in proximity of a pumping site of the endoplasmic reticulum. The quasi direct transfer of Ca2+ from the extracellular medium into the lumen of the e.r. would be a specific feature insured by T channels, not by other voltage-operated calcium channels. The e.r. would then act as a sort of Ca2+ pipeline, carrying the cation to the proximity of mitochondria, where it would be released, upon activation of the inositol 1,4,5-trisphosphate receptor, before being immediately and avidly taken up by the organelle. A strict structural organization must be maintained at each extremity of the pipeline in order to optimize the specificity and the efficacy of this signal transduction.

Both functional and structural evidences supporting this model of calcium transport within steroidogenic glomerulosa cells are reviewed in the present article.

Introduction

While low threshold T-type calcium currents have been recorded in a variety of excitable and non excitable cells since three decades, the cloning of the channels carrying these currents has been successfully achieved only in 1998 [1]. This delay in the molecular characterization of the channel, together with the lack of highly specific pharmacological tools have hampered for a long time the investigation of the physiological role of these channels, as well as of their involvement in pathological situations. Among the multiple roles proposed for these channels, and in spite of the important limitations just mentioned, the involvement of T channels in the modulation of adrenal steroid biosynthesis and secretion has been characterized quite early and extensively. The present article reviews evidences in favor of a role for T channels in the control of steroidogenesis, and more specifically aldosterone biosynthesis, describes how intramitochondrial calcium is involved in this control, and finally analyzes recent data suggesting the existence of a physical and functional link between T channels and mitochondria.

Section snippets

T channel expression and regulation in the adrenal cortex

Although most studies of T current expression have focused on the analysis of neural and cardiac tissues, the presence of similar currents has been demonstrated throughout the body in both excitable and non excitable cells, including adrenal glomerulosa [2], [3], [4], [5], [6], [7], [8], [9] and fasciculata cells [10], [11], [12], [13] from various species.

The analysis of the expression pattern of the various T channel isoforms revealed that mRNA for each of the three low voltage-activated

Relationship between T channel activity and steroidogenesis

Aldosterone secretion from adrenal glomerulosa cells is under the control of AngII and extracellular potassium [44], [45], and indirectly regulates blood pressure through stimulation of renal sodium reabsorption. A dysregulation of aldosterone production may lead to systemic hypertension and hypokalemia [46].

Adrenocortical T-type currents have been implicated early in the control of steroid biosynthesis [4], [11], [38], [47], [48] and this specific role for T channels has been extensively

Role of mitochondrial calcium in the control of steroidogenesis

Mitochondria play a particular role in Ca2+ homeostasis. Indeed, because of the very negative potential of their inner membrane (around −180 mV, due to proton extrusion by the respiratory chain), and due to the presence in this membrane of a specific Ca2+ uniporter, they avidly take up Ca2+ when its concentration rises in the cytosol. Mitochondrial Ca2+ influx is immediately balanced by an equivalent efflux out of the organelle, which is dependent on sodium exchange, but only up to a given

A model proposing a functional link between T channels and mitochondria

Because Ca2+ is known to modulate the rate of steroid biosynthesis at the mitochondrial level [67], and because Ca2+ entering the cell through T channels is not detected within the cytosol of bovine adrenal glomerulosa cells [38], we have proposed that Ca2+ is directly conveyed from the plasma membrane to the mitochondria through the endoplasmic reticulum (e.r.), which would act as a sort of Ca2+ pipeline [73]. Indeed, the respective distribution of e.r. and mitochondria in adrenal glomerulosa

Conclusion and perspective

Both toxicity and polyvalence of Ca2+ in signaling require a strong confinement of this cation within the cell. The apparent specificity of some Ca2+ channels for controlling particular functions is often linked to their ability to transport Ca2+ precisely to its site of action, as clearly demonstrated for L-type channels in muscle and for N-type channels in neuronal cells. In the case of steroidogenic cells, the mitochondrion is a main target for Ca2+. Because of the distance between the

Acknowledgements

I am grateful to Prof. Alessandro M. Capponi for his useful comments after reading the present manuscript. Bovine glomerulosa cell electron microscopy images have been obtained by Dr. Andres Maturana and Mr. Marc Mordasini, while ratio pericam images have been recorded with the help of Prof. Nicolas Demaurex and Dr. Serge Arnaudeau. Rabbit antibody raised against the type 1 IP3-R employed for immunogold labeling was a generous gift from Dr. Jan Paris, University of Leuven. Part of this work has

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