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

Institute of Anatomy and Cell Biology (D.M., M.P., R.M.), Justus-Liebig-University, 35385 Giessen, Germany; Institute for Hormone and Fertility Research (D.M., L.C.-D., L.T.B., B.B.-S., A.K.M.), University of Hamburg, 20251 Hamburg, Germany; and Department of Pharmacology (R.C.S.), University of Mississippi, University, Mississippi 38677

Address all correspondence and requests for reprints to: Dr. Dieter Müller, Institute of Anatomy and Cell Biology, Justus-Liebig-University, Aulweg 123, 35385 Giessen, Germany. E-mail: hans-dieter.mueller{at}anatomie.med.uni-giessen.de.

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.