Role of phospholipases in adrenal steroidogenesis

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   Figure 1

   The reactions catalyzed by phospholipases C, D, and A₂. In adrenocortical cells treated with agonists such as angiotensin II (AngII), endothelin-1 (ET1), sphingosine 1-phosphate (S1P), carbachol, vasopressin (VP), and neuropeptide B (NPB), activated phospholipase C (PLC) cleaves on one side of the phosphate linker, as indicated, to produce diacylglycerol and the phosphorylated head group. In contrast, phospholipase D (PLD) hydrolyzes the phospholipid on the other side of the phosphate linker to generate phosphatidic acid and the headgroup; in adrenocortical cells, PLD has been demonstrated to be activated by AngII, S1P, carbachol, very-low-density lipoprotein (VLDL), phorbol esters, and an elevated extracellular potassium concentration (K+). Finally, as illustrated, phospholipase A₂ (PLA₂) removes the fatty acid from the 2 position of the glycerol backbone of a phospholipid, whereas PLA₁ deacylates the phospholipid at position 1 (not shown). The products resulting from this activity are a lysophospholipid and a free fatty acid. The fatty acids can be further metabolized to bioactive lipids such as eicosanoids.
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   Figure 2

   The phosphoinositide-specific phospholipase C pathway. The action of phosphoinositide-specific PLC on phosphatidylinositol 4,5-bisphosphate (PIP₂) releases inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binds to IP₃ receptors to release calcium from the endoplasmic reticulum and increase intracellular calcium levels. The elevated cytosolic calcium concentration activates calcium/calmodulin-dependent protein kinases, calpains (calcium-sensitive proteases), calcium-activated potassium channels, and classical protein kinase C isoenzymes. At the same time, DAG in the membrane activates various effectors such as classical and novel protein kinase C isoenzymes, protein kinase D isoenzymes, guanine nucleotide exchange factors for Ras called Ras guanine nucleotide release proteins (RasGRPs), chimaerins (Rho GTPase-activating proteins), and UNC-13 proteins involved in vesicle exocytosis. Effectors for PA include the nuclear hormone receptor steroidogenic factor-1 (SF1), the PIP₂-synthesizing enzyme phosphatidyinositol 4-phosphate 5-kinase, the cAMP-degrading enzyme phosphodiesterase 4D3 (PDE4D3), mammalian target of rapamycin (mTOR), the small GTP-binding proteins c-Raf and Rac, protein phosphatase-1 (PP1), Src homology region 2 domain-containing phosphatase-1 (SHP1), kinase suppressor of Ras (KSR), protein kinase C-α (PKC-α), son of sevenless (SOS), G_oα, and ribosomal S6 kinase (reviewed in Selvy et al. 2011).
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   Figure 3

   Phospholipase D-catalyzed reactions, lipid signals, and effectors. Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine in the presence of water to produce phosphatidic acid (PA) or a transphosphatidylation of phosphatidylcholine in the presence of a primary alcohol such as ethanol to generate the phosphatidylalcohol (e.g. phosphatidylethanol, PEt) and choline (Cho). PEt is not readily metabolized; however, PA can be dephosphorylated by lipid phosphate phosphatases (LPPs) to yield DAG (with effectors as indicated in Fig. 2) or deacylated to release the free fatty acid and generate lysophosphatidic acid (LPA), which can activate G protein-coupled LPA receptors. DAG can also be phosphorylated by DAG kinases (DAGK) to give PA (with effectors also as indicated in Fig. 2) or deacylated to monoacylglycerol (MAG) with the release of a fatty acid by DAG lipase (DAGL).

• © 2016 Society for Endocrinology