ReviewA brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis
Introduction
Steroidogenesis is the process by which important steroid hormones are synthesized by specific tissues and cells in the body. Examples of these important steroids are the glucocorticoids that are synthesized in the adrenal cortex, the mineralocorticoids that are synthesized in the adrenal glomerulosa, the ovarian and placental progestins and estrogens, the testicular androgens and several neurosteroids such as pregnenolone, progesterone, 5α-dihydroprogesterone, allopregnanolone and DHEA, that are synthesized in the brain. The adrenal glucocorticoids serve to regulate carbohydrate metabolism and manage stress and the mineralocorticoids are involved in salt balance and the maintenance of blood pressure. Ovarian progesterone and estrogen are involved in the maintenance of female secondary sex characteristics and reproductive function while testicular testosterone is involved in maintaining male secondary sex characteristics and is essential for male fertility. Neurosteroid functions include stimulation of GABAergic responses, modulation of the response of Purkinje cells to excitatory amino acids and the enhancement of memory function. Other tissues and cells have also been reported to have the capacity for de novo steroid synthesis, but the localization of where steroids are synthesized and their respective functions are not the main focus of this review. Rather, this review will concentrate on the manner in which the synthesis of steroid hormones are regulated and the history of the efforts that have been made to uncover the components and the mechanisms involved in this regulation. This history dates back approximately six decades when it was first observed that the synthesis of steroid hormones in vitro could be stimulated with trophic hormones and that this synthesis required the production of a new protein(s), as will be described later in this review. This singular observation formed the basis for what has been a long and most interesting search for the putative regulatory protein(s). We will briefly summarize the early studies that were performed in the search for this regulatory protein(s), the necessary characteristics of the candidates required to perform this function and some of the controversies that have arisen along the way, and indeed, remain to the present time. To be sure, this has been an interesting undertaking by a number of investigators in the field and it would seem safe to say that at this juncture in time, the entire story of what factors are involved in the acute regulation of steroid hormone biosynthesis and how they function is not yet completely understood.
Section snippets
Characteristics of the regulation of steroid hormone biosynthesis
The initial step in steroidogenesis is the conversion of cholesterol to the first steroid formed, pregnenolone, which occurs in all steroidogenic tissues (Miller, 1988, Pescador et al., 1997). This conversion is a result of the action of the cytochrome P450 side-chain cleavage enzyme (P450scc; CYP11A1), that is part of the cholesterol side chain cleavage system that resides on the matrix side of the inner mitochondrial membrane (Farkash et al., 1986). Pregnenolone then exits the mitochondria
The Steroidogenic Acute Regulatory Protein
A candidate protein for the acute regulator of steroidogenesis was first described by Orme-Johnson and her colleagues as an ACTH-induced 30 kDa phosphoprotein in hormone-treated rat and mouse adrenocortical cells, and as an LH-induced protein in rat corpus luteum cells and mouse Leydig cells (Alberta et al., 1989, Epstein and Orme-Johnson, 1991a, Epstein and Orme-Johnson, 1991b, Krueger and Orme-Johnson, 1983, Pon et al., 1986a, Pon et al., 1986b, Pon and Orme-Johnson, 1988). These studies
The Peripheral Benzodiazepine Receptor (PBR)/Translocator Protein (TSPO)
The Peripheral Benzodiazepine Receptor (PBR), whose name was recently changed to the Translocator Protein (TSPO; hereafter referred to as TSPO in this review) was first described in the late 1970s (Gavish et al., 1999). TSPO was demonstrated to have high binding affinity for benzodiazepines but was a distinctly different receptor from the central benzodiazepine receptor, the γ-aminobutyric acid type A receptor/GABAA receptor. Since that time there have been numerous studies involving TSPO that
Controversies in the regulation of cholesterol transfer and steroidogenesis
A brief summary of the studies that have been performed in determining the roles of StAR and TSPO in regulating cholesterol transport to the IMM and thus stimulating steroid biosynthesis is given above. There have been a number of models proposed for the actions of each of these proteins. Some of the models have been challenged as a result of direct experimentation that demonstrated the mechanisms that they proposed to be unlikely, as were the cases with the candidate proteins SCP2 and SAP.
Funding
This work was funded by the National Institutes of Health Grant # HD17481 (DMS), Grant B1-0028 from the Robert A. Welch Foundation (DMS) and startup funds from Cornell University (VS).
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Present address: Department of Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan.