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J. Biol. Chem., Vol. 278, Issue 49, 48880-48889, December 5, 2003

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Regulation of the Guanylyl Cyclase-B Receptor by Alternative Splicing^*

Naohisa Tamura and David L. Garbers¶||

From the Cecil H. and Ida Green Center for Reproductive Biology Sciences, the Department of Pharmacology, and the ^¶Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041

Guanylyl cyclase-B (GC-B) is a single transmembrane receptor that binds C-type natriuretic peptide (CNP). The ligand/receptor appears critical in the regulation of cell proliferation and differentiation where it acts as an adversary of mitogenic signaling pathways. We have isolated three guanylyl cyclase-B isoforms generated from a single gene by alternative splicing and termed them GC-B1, GC-B2, and GC-B3. GC-B1 is full-length and responds maximally to CNP, GC-B2 contains a 25-amino acid deletion in the protein kinase homology domain, and GC-B3 only retains a part of the extracellular ligand-binding domain. GC-B2 binds CNP, but the ligand fails to activate the cyclase, while GC-B3 fails to bind ligand. When GC-B2 or GC-B3 is expressed coincident with GC-B1, they act as dominant negative isoforms by virtue of blocking formation of active GC-B1 homodimers. Relative expression levels of GC-B1, GC-B2, and GC-B3 vary across tissues and as a function of in vitro culture; the relative amount of GC-B2 to GC-B1 is repressed in cultured smooth muscle cells relative to endogenous ratios in the medial layer cells of the aorta. Thus, GC-B isoform levels can be independently regulated. Given that the splice variants serve as dominant negative forms, these will serve as regulators of the full-length GC-B.

Received for publication, August 6, 2003 , and in revised form, September 23, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY323832 and AY323833.

^* This work was supported in part by an award (to D. L. G.) from the Sandler Program for Asthma Research, the Howard Hughes Medical Institute, and the Cecil H. and Ida Green Center for Reproductive Biology Sciences. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-5090; Fax: 214-648-5087; E-mail: David.Garbers{at}UTSouthwestern.edu.

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