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