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.
Highlights
Water homeostasis is one of the most tightly regulated physiological events in the human body [1]
When co-expressing mSCTR and mAVPR2 in vitro, upon stimulation of a graded concentration of SCT (1 pM to 10 μM), SCT-induced cAMP production was potentiated (Fig 3A; Emax from 98.75 ±0.72 to 152.50±0.29% and EC50 from 51.44±9.92 to 2.49±0.25 nM), while no significant changes were found in control cells co-expressing mSCTR and mAVPR1b
The signaling modification observed in the present study illustrates the importance of G protein-coupled receptors (GPCRs) heteromer in affecting cellular physiology
Summary
Water homeostasis is one of the most tightly regulated physiological events in the human body [1]. In addition to the well-recognized Vp axis, the existence of Vp-independent mechanisms in regulating water reabsorption is confirmed [2,3,4,5,6,7,8,9,10,11,12]. SCT was discovered to be a neurohypophysial factor secreted alongside Vp in the posterior pituitary to control fluid balance by stimulating Vp expression and release from the hypothalamic paraventricular nucleus [11]. SCT stimulates water reabsorption in the kidney via activating the cAMP signaling pathway and subsequently AQP2 trafficking in the kidney distal collecting duct cells [12]. Over 170 different mutations were discovered leading to various degree of impairment in kidney’s responsiveness to Vp stimulation [14].
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