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

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.

Oligomerization of Family B GPCRs: Exploration in Inter-Family Oligomer Formation.

G-protein-coupled receptors (GPCRs) are classified into A to F subfamilies in which only families A, B, and C are present in mammals. Some of these GPCRs were found to form higher ordered structures such as oligomers with the discovery of interacting receptors in the form of homomers or heteromers. The importance of these oligomers on regulating receptor functions has recently been an intense research focus. It has been proposed that receptor oligomer formation has impact on its physiological importance on receptor trafficking, signaling, ligand-related regulation, and also is related to certain diseases. The present body of knowledge, however, comprises mainly intra-family oligomers formation and their consequences. Inter-family oligomers are recognized but there is limited information. This article aims to provide a current view regarding inter-family GPCR oligomerization in the subfamilies A, B, and C found in mammals.

Orexins and their receptors from fish to mammals: a comparative approach.

Although recently discovered, orexins have been rapidly established as important neuropeptides in regulating physiological processes including food intake, sleep/wake cycles and reproduction through binding to two class B G protein-coupled receptors (OX1R and OX2R). To date, a handful of sequences for orexins and their receptors ranging from fish to mammalian species have been identified, allowing a glimpse into their evolution. Structurally, the genetic and molecular organization of the peptides and receptors amongst vertebrates are highly similar, underlining the strong evolutionary pressure that has been exerted to preserve structure and ultimately function. Furthermore, the absence of invertebrate orexin-like sequences suggests early vertebrates as the origin from which orexins evolved. With respect to the receptors, OX2R is probably evolutionary more ancient whilst OX1R is specific to mammalian species and evolved only during this later lineage. In common to all vertebrates studied, the hypothalamus remains to be the key brain region in which orexinergic neurons and fibers are localized in, establishing orexin to be an important player in regulating physiological processes especially those related to food intake and energy metabolism. To allow better understanding of the evolution of orexins and their receptors, this review will provide a comparative approach to their structures and functions in vertebrates.