Signaling Modification by GPCR Heteromer and Its Implication on X-Linked Nephrogenic Diabetes Insipidus

• Published in: PloS one Vol. 11; no. 9; p. e0163086
• Main Authors: Ng, Hans K H, Harikumar, Kaleeckal G, Miller, Laurence J, Chow, Billy K C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.09.2016; Public Library of Science (PLoS)
• Subjects: Animals; Aquaporin 2; Aquaporins; Biology and Life Sciences; Body water; Cell surface; CHO Cells; Collecting duct; Cricetinae; Cricetulus; Cyclic adenosine monophosphate; Diabetes; Diabetes insipidus; Diabetes Insipidus, Nephrogenic - genetics; Diabetes Insipidus, Nephrogenic - metabolism; Diabetes mellitus; G protein-coupled receptors; Gene Expression; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - metabolism; Homeostasis; Humans; Inspection; Kidneys; Ligands; Medicine and Health Sciences; Mice; Microscopy, Confocal; Mutation; Nondestructive testing; Pharmacology; Protein Binding; Protein Multimerization; Proteins; Reabsorption; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Gastrointestinal Hormone - chemistry; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; Receptors, Vasopressin - chemistry; Receptors, Vasopressin - genetics; Receptors, Vasopressin - metabolism; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Secretin; Signal Transduction - genetics; Signaling; Urine; Vasopressin; Hong Kong; United States > US; China; Arizona
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0163086

The involvement of secretin (SCT) and secretin receptor (SCTR) in regulating body water homeostasis is well established. Identified as one of the vasopressin (Vp)-independent mechanisms in fluid balance, SCT regulates aquaporin 2 (AQP2) in the kidney distal collecting duct cells through activating intracellular cAMP production. This ability to bypass Vp-mediated water reabsorption in kidney implicates SCT's potential to treat nephrogenic diabetes insipidus (NDI). Research on NDI in the past has largely been focused on the searching for mutations in vasopressin receptor 2 (AVPR2), while the functional relationship between SCTR, AVPR2 and NDI remains unclear. Here, we demonstrate the interaction between SCTR and AVPR2 to modulate cellular signaling in vitro. Interestingly, we show in this report that upon heteromer formation with SCTR, R137H, a NDI-causing AVPR2 mutant that is defective in trafficking to cell surface, can functionally be rescued. Our data may provide an explanation for this clinically mild case of NDI, and insights into the pathological development of NDI in the future.