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Vol. 57, Issue 2, 259-267, February 2000

Functional Domains and Expression of Truncated Atrial Natriuretic Peptide Receptor-A: The Carboxyl-Terminal Regions Direct the Receptor Internalization and Sequestration in COS-7 Cells

Kailash N. Pandey, Ravindra Kumar, Ming Li, and Huong Nguyen

Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana and Medical College of Georgia, Augusta, Georgia.

The objective of this study was to determine the role of cytoplasmic (protein kinase-like homology and guanylyl cyclase catalytic) domains of atrial natriuretic peptide (ANP) receptor-A (Npra) in postbinding events and metabolic turnover of ligand-receptor complexes. Using deletion mutagenesis, the specific regions in the intracellular domains of Npra relevant to the receptor function, namely ligand-binding, cGMP production, and internalization and sequestration of ligand-receptor complexes, have been determined in transiently expressing COS-7 cells. Deletion of 12 aa (aa) at the carboxyl-terminal end of receptor (Delta 1045-Npra) affected neither ligand-binding efficiency nor cGMP production. However, deletion of 120 to 170 aa residues (Delta 937-Npra, Delta 916-Npra, Delta 902-Npra, and Delta 887-Npra) decreased ligand binding by 16 to 20% and cGMP production by 50 to 90%. Further deletion of 422 aa and 569 aa (Delta 635-Npra and Delta 488-Npra) reduced ligand binding efficiency by 40% and 90%, respectively. The deletion of 12 aa (Delta 1045-Npra) did not affect the internalization of Npra; however, deletions up to 170 aa (Delta 937-Npra, Delta 916-Npra, Delta 887-Npra) reduced the internalization of ligand-receptor complexes by 60%. Cells expressing either full-length (wild-type) Npra or 120 aa deleted receptor (Delta 937-Npra) released 40 to 45% 125I-ANP radioactivity into culture medium, but only 10 to 15% radioactivity was released from the cells that expressed Delta 635-Npra. Furthermore, 35 to 40% 125I-ANP radioactivity was detected into the intracellular compartments of cells that expressed the wild-type Npra, and only 5 to 10% 125I-ANP radioactivity was observed in cells expressing the Delta 635-Npra (-422 aa) or Delta 488-Npra (-569 aa) mutant receptors. These results show that specific regions within the intracellular domains of Npra determine the extent of ligand-binding efficiency, cGMP production, endocytosis, and intracellular sequestration of ligand-receptor complexes in cDNA expressing COS-7 cells.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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