title: Homologous and lysophosphatidic acid-induced desensitization of the atrial natriuretic peptide receptor, guanylyl cyclase-A, in MA-10 leydig cells.
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.
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany. hans-dieter.mueller@anatomie.med.uni-giessen.de
authors.forename: Dieter
authors.initials: D
authors.lastname: Müller
authors.forename: Lourdes
authors.initials: L
authors.lastname: Cortes-Dericks
authors.forename: Lygia T
authors.initials: LT
authors.lastname: Budnik
authors.forename: Bärbel
authors.initials: B
authors.lastname: Brunswig-Spickenheier
authors.forename: Maria
authors.initials: M
authors.lastname: Pancratius
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.forename: Amal K
authors.initials: AK
authors.lastname: Mukhopadhyay
authors.forename: Ralf
authors.initials: R
authors.lastname: Middendorff
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006152:Cyclic GMP / Q000096:biosynthesis; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006162:Guanylate Cyclase / Q000187:drug effects*; D007984:Leydig Cell Tumor / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects*
chemical_list: D008246:Lysophospholipids; D009320:Atrial Natriuretic Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP; C032881:lysophosphatidic acid