Homologous and Lysophosphatidic Acid-Induced Desensitization of the Atrial Natriuretic Peptide Receptor, Guanylyl Cyclase-A, in MA-10 Leydig Cells

• Published in: Endocrinology (Philadelphia) Vol. 147; no. 6; pp. 2974 - 2985
• Main Authors: Müller, Dieter, Cortes-Dericks, Lourdes, Budnik, Lygia T, Brunswig-Spickenheier, Bärbel, Pancratius, Maria, Speth, Robert C, Mukhopadhyay, Amal K, Middendorff, Ralf
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.06.2006
• Subjects: Animals; Atrial Natriuretic Factor - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - physiology; Cyclic GMP - biosynthesis; Cyclic GMP-Dependent Protein Kinases - physiology; Extracellular Signal-Regulated MAP Kinases - metabolism; Fundamental and applied biological sciences. Psychology; Guanylate Cyclase - drug effects; Leydig Cell Tumor - metabolism; Lysophospholipids - pharmacology; Male; Mice; Phosphorylation; Receptors, Atrial Natriuretic Factor - drug effects; Vertebrates: endocrinology; Natriuretic hormone; Desensitization; Lysophosphatidic acid; Enzyme; Phosphorus-oxygen lyases; Lyases; Atrial natriuretic peptide; Testicle; Guanylate cyclase; Male genital system; Leydig cell; Biological receptor
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-0092

The cardiac hormone atrial natriuretic peptide (ANP) signals via interaction with a plasma membrane receptor, which has guanylyl cyclase (GC) activity and is referred to as GC-A. Desensitization of GC-A is thought to represent a physiologically important regulatory mechanism, but the signaling pathways implicated and cell type-specific effects are still poorly understood. Here we demonstrate that sustained exposure to either ANP itself or the bioactive lipid lysophosphatidic acid (LPA) elicits GC-A desensitization in MA-10 Leydig cells. Both reactions show similar kinetics and evoke equal decreases (by 40%) in GC-A hormone responsiveness. Homologous (ANP induced) desensitization, in which cGMP is generated as second messenger, is blocked by distinct cAMP-dependent protein kinase [protein kinase A (PKA)] inhibitors, H 89, and Rp-8-CPT-cAMPs, providing evidence that PKA mediates the reaction. Accordingly, the ANP/cGMP-elicited effects are mimicked by a cAMP analog, 8-bromo-cAMP. The LPA-induced (heterologous) desensitization is not blocked by PKA inhibition, indicating a different signaling pathway. LPA, but not ANP, enhances ERK phosphorylation and induces cell rounding together with a dramatic reorganization of actin filaments. Consistent with the identification of LPA receptor (LPA2 and LPA3) gene expression, the findings are indicative of LPA receptor-mediated reactions. This study demonstrates for the first time coexistence of homologous and heterologous desensitization of GC-A in the same cell type, reveals that these reactions are mediated by different pathways, and identifies a novel cross talk between phospholipid and natriuretic peptide signaling. The morphoregulatory activities exerted by LPA suggest a crucial role for Leydig cell physiology.