Homologous and Lysophosphatidic Acid-induced Desensitization of the Atrial Natriuretic Peptide Receptor, Guanylyl Cyclase-a, in Ma-10 Leydig Cells.
From: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany. hans-dieter.mueller@anatomie.med.uni-giessen.de
Endocrinology
- Publish Date: Jun 2006
- ISSN: 0013-7227
- Volume: 147
- Issue: 6
- Pages: 2974-85
- Medium: Print
- Language: English
- Citation (JAMA): Müller Dieter, Cortes-Dericks Lourdes, Budnik Lygia T, et al. Homologous and Lysophosphatidic Acid-induced Desensitization of the Atrial Natriuretic Peptide Receptor, Guanylyl Cyclase-a, in Ma-10 Leydig Cells.. Endocrinology Jun 2006;147:2974-85
Abstract
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.
Mesh Headings (Keywords): Animals, Atrial Natriuretic Factor, Cell Line, Tumor, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Extracellular Signal-Regulated MAP Kinases, Guanylate Cyclase, Leydig Cell Tumor, Lysophospholipids, Male, Mice, Phosphorylation, Receptors, Atrial Natriuretic Factor
Check for Full Text / PubMed Unique Identifier (PMID): 16527839
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