Investigation on Pathophysiological Significance of Dominant Negative Isoforms of Natriuretic Peptide Receptors

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C-type natriureitc peptide (CNP) utilizes guanylyl cyclase (GC) -B as a receptor to inhibit proliferative vascular lesions and to promote endochondral ossification. We have shown that three GC-B isoforms (GC-B1, B2, B3) are generated from the single GC-B gene in mice and that GC-B2 lacking a regulatory region and GC-B3 constituted by an extracellular region only serve as dominant negative isoforms against the CNP-induced increase of intracellular cGMP levels by GC-B1. A reverse transcription and PCR analysis showed that most of GC-B mRNA species in the growth plate cartilage were GC-B1, while expression levels of GC-B2 and GC-B3 are almost equal to the expression level of GC-B1 mRNA in the central nervous system. This observation could explain why the most prominent phenotype of GC-B null mice is dwarfism where the GC-B mRNA level as the sum of three isoforms in the growth plate cartilage is much less than in the cetral nervous system. We investigated if GC-B2 or GC-B3 isoforms were expressed in human tissues, and confirmed that at least GC-B2 isoform is expressed in the human heart Our data indicated that a new GC-B isoform is generated by retaining intron 8, which contains an in-frame stop codon and the isoform is consisted by an extracellular domain, a transmembrane segment, and a short intracellular segment. The expected molecule resembles the molecule generated by a nonsense mutation at GIn500 of human GC-B gene, which causes acromesomelic dysplasia, type Maroteaux.