Skip to main content
. 2018 Dec 19;2:2470547018818555. doi: 10.1177/2470547018818555

Figure 2.

Figure 2.

Schematic depicting the activation of a steroidogenic cell with ACTH or LH. In the adrenal gland, ACTH binds to the GPCR melanocortin 2 receptor (MC2R), whereas in the gonads, LH binds to the GCPR LH/choriogonadotropin receptor (LHCGR).103 Upon ligand binding to MC2R or LHCGR, these receptors mediate a signaling cascade through their associated G-protein. The Gαs subunit of the cell membrane-bound G-protein binds guanosine triphosphate (GTP) and dissociates from the G-protein in order to activate adenylyl cyclase which converts ATP to 3′,5′-cyclic AMP (cAMP). The increase in cAMP levels activates protein kinase A (PKA). Meanwhile, the Gβγ subunit of the membrane-bound G-protein activates phospholipase C β (PLCβ), which cleaves diacylglycerols (DAG) from the plasma membrane. The increase in DAG levels activates PKC. Acute changes secondary to this activation include the phosphorylation of StAR and TSPO, which allows for a higher influx of cholesterol across the mitochondrial membranes allowing for increased steroidogenesis. PKA phosphorylates and activates cAMP responsive element binding protein (CREB), which binds to cAMP response elements (CREs) to promote transcription of several downstream genes involved in neurosteroidogenesis.102 CREs have been identified in the promoters of HMG-CoA reductase, NPC1, StAR, and P450scc.49,102,104,105 PKC also has been shown to activate two transcription factors: steroidogenic factor 1 (SF-1) and activating protein 1 (AP-1).102 SF-1 binding domains have been found in the promoters of NPC1, StAR, P450scc, and 3β-HSD2.102,106,107 AP-1 binding domains have been found in the promoters of TSPO, P450scc and 3β-HSD2.49,62,102 The Nuclear Receptor 4A (NR4A) family of transcription are involved in inflammation and have been shown to upregulate StAR and 3β-HSD2.108–111 Long-term changes include activation of transcription factors which upregulate the transcription of genes associated with allopregnanolone synthesis. OMM: outer mitochondrial membrane; IMM: inner mitochondrial membrane; IMS: intermembrane space; HMG-CoA: 3-hydroxy-3-methylglutaryl CoA; NPC1: Niemann Pick type C1.