Alternative Splicing of the Guanylyl Cyclase-A Receptor Modulates Atrial Natriuretic Peptide Signaling
| Autor: | Michael Hartmann, Michaela Kuhn, Birgit Gassner, Viacheslav O. Nikolaev, Juliane Schröter, Moritz Bünemann, Alexandra Gazinski, Boris V. Skryabin, Thomas Müller |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Biology Models Biological Biochemistry Cell Line Mice Exon Atrial natriuretic peptide Internal medicine medicine Animals Humans Receptor Cyclic GMP Lung Molecular Biology Messenger RNA Angiotensin II Mechanisms of Signal Transduction Alternative splicing Cell Biology Rats Cell biology Mice Inbred C57BL Alternative Splicing Endocrinology RNA splicing cardiovascular system Signal transduction Peptides Receptors Atrial Natriuretic Factor Atrial Natriuretic Factor hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 283:28313-28320 |
| ISSN: | 0021-9258 |
| Popis: | Atrial (ANP) and B-type natriuretic peptides (BNP) modulate blood pressure and volume through the stimulation of cyclic GMP production by their guanylyl cyclase-A (GC-A) receptor. A novel isoform of GC-A has been identified that is the result of differential splicing of exon 4. The deletion of a 51-bp sequence is predicted to delete 17 amino acids (Lys314–Gln330) in the membrane-distal part of the extracellular domain. Reverse transcription-PCR analyses demonstrated low messenger RNA expression levels of spliced GC-A in all tissues. Homology modeling suggested that the alterations in the protein structure could interfere with ANP binding or signaling. Indeed, functional studies in transfected HEK 293 cells demonstrated that binding of ANP and ANP-induced cyclic GMP formation by GC-AΔLys314-Gln330 were totally abolished. Furthermore, cotransfection studies showed that this GC-A variant forms heterodimers with the wild type receptor and inhibits ligand-inducible cGMP generation. Finally, treatment of mice with angiotensin II (300 ng/kg/min during 7 days) resulted in enhanced pulmonary mRNA expression of spliced GC-A, which was concomitant to diminished GC-A/cGMP responses to ANP. We conclude that alternative splicing can regulate endogenous ANP/GC-A signaling. Angiotensin II-induced alternative splicing of GC-A may represent a novel mechanism for reducing the sensitivity to ANP. |
| Databáze: | OpenAIRE |
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