title: Signaling Modification by GPCR Heteromer and Its Implication on X-Linked Nephrogenic Diabetes Insipidus.
abstract: 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.
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Hans K H
authors.identifier: http://orcid.org/0000-0002-4262-5936
authors.initials: HK
authors.lastname: Ng
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona, 85259, United States of America.
authors.forename: Kaleeckal G
authors.initials: KG
authors.lastname: Harikumar
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona, 85259, United States of America.
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
authors.affiliation: School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Billy K C
authors.initials: BK
authors.lastname: Chow
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D017483:Receptors, Vasopressin; C029937:secretin receptor