Abstract
Background Activation of the homodimeric transmembrane guanylyl cyclase-A (GC-A) receptor upon binding of its extracellular ligands, atrial (ANP) and B-type (BNP) natriuretic peptides, leads to cyclic GMP formation in many types of cells. This NP/GC-A pathway has a critical role in the endocrine regulation of arterial blood pressure and volume and in the local counter-regulation of cardiac hypertrophy and fibrosis. Alterations of this system result in arterial hypertension, hypervolemia and cardiac hypertrophy. Many studies have shown that exposure of GC-A to high concentrations of ANP/BNP or to growth hormones such as angiotensin II (Ang II) or endothelin provokes homologous versus heterologous desensitization of the receptor [1]. However, the mechanisms accounting for this loss of function of GC-A in vivo are largely unknown. In the present study we identified and characterized a novel isoform of GC-A (GC-AΔLys-Gln 330) with unique structural properties. Our data reveal that this splice variant functions as dominant negative isoform and suggest that increased alternative splicing of GC-A may contribute to homologous or heterologous desensitization of the NP/GC-A system.
Highlights
Activation of the homodimeric transmembrane guanylyl cyclase-A (GC-A) receptor upon binding of its extracellular ligands, atrial (ANP) and B-type (BNP) natriuretic peptides, leads to cyclic GMP formation in many types of cells
In the present study we identified and characterized a novel isoform of GC-A (GC-AΔLys314-Gln 330) with unique structural properties
Our data reveal that this splice variant functions as dominant negative isoform and suggest that increased alternative splicing of GC-A may contribute to homologous or heterologous desensitization of the NP/GC-A system
Summary
Activation of the homodimeric transmembrane guanylyl cyclase-A (GC-A) receptor upon binding of its extracellular ligands, atrial (ANP) and B-type (BNP) natriuretic peptides, leads to cyclic GMP formation in many types of cells. This NP/GC-A pathway has a critical role in the endocrine regulation of arterial blood pressure and volume and in the local counter-regulation of cardiac hypertrophy and fibrosis. Our data reveal that this splice variant functions as dominant negative isoform and suggest that increased alternative splicing of GC-A may contribute to homologous or heterologous desensitization of the NP/GC-A system
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