Alternative splicing of the guanylyl cyclase-A receptor modulates
atrial natriuretic peptide signaling
J Biol Chem, 283 (42):
28313-20 (October 2008)Hartmann, Michael Skryabin, Boris V Muller, Thomas Gazinski, Alexandra
Schroter, Juliane Gassner, Birgit Nikolaev, Viacheslav O Bunemann,
Moritz Kuhn, Michaela Research Support, Non-U.S. Gov't United States
The Journal of biological chemistry J Biol Chem. 2008 Oct 17;283(42):28313-20.
Epub 2008 Aug 18..Abstract
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-ADelta(Lys314-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.