Molecular interaction of mouse secretin and angiotensin II receptors and their potential implications in water homeostasis

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	Molecular interaction of mouse secretin and angiotensin II receptors and their potential implications in water homeostasis
	Chow, BKC; Ng, SYL; Lee, T. O.
	2012-11-29
Source Publication	20th International Symposium on Regulatory Peptides (REGPEP2014)
Abstract	Osmoregulation is critical to life and is tightly regulated by three major hormones namely secretin (SCT), angio- tensin II (ANGII) and vasopressin (VP). Of note, SCT and ANGII share overlapping physiological roles includ- ing similar expression pattern within the brain, dipsogenic actions and activation of VP expression and/or release in mice. However, it remains unclear how their receptor pathways may cross-interact to aid osmoregulation. In recent years, GPCR oligomerization has been implicated to play roles in regulating process- es. This project aims to explore the molecular associa- tion between SCTR and ANGII receptors by biolumi- nescence resonance energy transfer (BRET) assays that revealed SCTR and ANGII type 1a receptor (AT1aR) to form hetero-complexes. This oligomerization event was found by BRET competition to be contributed predom- inantly by transmembrane (TM) domain regions 2 and 4 in SCTR, and TM1 and TM4 in AT1aR. Within which, combinational use of mutant TM peptides and SCTR chi- meras revealed the importance of lipid-exposed residues, par- ticularly Leu204 and Ser205 in SCTR TM2 as key contact points for formation of the SCTR/AT1aR complex. Morpho- logically, the heteromers were visualized by confocal and FRET imaging at the cell surface and found have a role in modulating AT1aR trafficking. It was also found that the SCTR/AT1aR complex affected Gαs signaling specifically, reducing maximal response values by 24.3 ± 2.8 % compared to CHO-K1 cells transfected with only SCTR. While, this negative effect could be abolished by co-application of SCT and ANGII peptides, use of constitutively active AT1aR mu- tants or disruption of the hetero-complex using SCTR mutants. Taken together, the SCTR/AT1aR complex was proposed to impose conformational restraints on the SCTR that could be overcome upon activation of the AT1aR. Physiologically, hyperosmolality isovolemic induced drinking could be attenu- ated by central administration of TM peptides and the phos- pholipase C pathway blocker H-89, indicating receptor oligo- merization to have a role in neural osmoregulation via a Gαs dependent pathway. This study presents novel findings regard- ing the receptor oligomerization of SCTR and AT1aR, which may be the molecular basis to the overlapping roles of SCT and ANGII in water homeostasis
Keyword	GPCR dimerization secretin AGTR1
URL	View the original
Language	英語English
The Source to Article	PB_Publication
PUB ID	51956
Document Type	Conference paper
Collection	DEPARTMENT OF BIOMEDICAL SCIENCES
Corresponding Author	Chow, BKC
Recommended Citation GB/T 7714	Chow, BKC,Ng, SYL,Lee, T. O.. Molecular interaction of mouse secretin and angiotensin II receptors and their potential implications in water homeostasis[C], 2012.
APA	Chow, BKC., Ng, SYL., & Lee, T. O. (2012). Molecular interaction of mouse secretin and angiotensin II receptors and their potential implications in water homeostasis. 20th International Symposium on Regulatory Peptides (REGPEP2014).

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