Acute Effects of LH

Two types of responses to LH are seen in Leydig cells. The acute response triggers a rapid production of steroid within minutes (46). In the acute LH signal transduction process, LH-Rs interact with intracytoplasmic adenylate cyclase to form the second messenger adenosine 3',5'-cAMP. A sharp increase in cytoplasmic cAMP levels elicits a cascade of events leading to testosterone synthesis, including increased translocation of cholesterol from the cytosol to the inner mitochondrial membrane, conversion of cholesterol to pregnenolone, and, ultimately, transformation of steroid intermediates into testosterone. In addition to stimulating cAMP formation, LH acts on other intracellular signaling systems, including release of calcium from internal stores, synthesis of arachidonic acid (AA) and its metabolites from membrane phospholipid, and efflux of chloride ions, which have all been linked to the steroidogenic process (80).

The acute response of Leydig cells to LH does not require new transcription of mRNA (81). However, carrier proteins are required in the cholesterol translocation process for the rapid steroid production in the acute response. StAR is a 30-kDa molecular weight cholesterol transporter, and blockade of its synthesis by cycloheximide prevents the LH-induced increase in testosterone biosynthesis (82). Transient transfec-tion of COS-1 cells with the cDNA for StAR increases the conversion of cholesterol to pregnenolone. StAR gene mutations result in the pathological condition of congenital lipoid adrenal hyperplasia (lipoid CAH), in which patients are unable to convert cholesterol to pregnenolone. This confirms a cholesterol-shuttling role for StAR protein in steroidogenesis (46,83,84). StAR protein biochemistry, as it is currently understood, may not completely account for transfer of cholesterol across mitochondrial membranes (85). Another candidate protein for cholesterol trafficking is the mitochondrial PBR, which is an 18-kDa integral outer mitochondrial membrane phosphoprotein that has a high affinity for cholesterol binding (86). PBR expression decreases are correlated with the decreased steroid synthesis (87). PBR plays a role in the maintenance of the basal pool of mitochondrial cholesterol (88). It has been postulated that PBR functions in cholesterol transport in steroidogenic tissues by mediating the entry, distribution, and/or availability of cholesterol within mitochondria (87,89). Recently, it was proposed by West et al. that PBR associates with StAR and that the two proteins may work in tandem at the outer mitochondrial membrane (90).

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