SCTR/AT1aR heteromer related osmoregulation in hypothalamus

Abstract

Emerging studies suggest that GPCR oligomerization could confer functional advantages to receptors and even constitute clinical applications. Recent study found that angiotensin II 1a receptors (AT1aR) and secretin receptors (SCTR) can form heteromer and participate in osmoregulation. Studying GPCR dimerization faces many technical challenges, including selectivity and specificity. Since transmembrane (TM) peptides can act as competitors against the interacting surfaces between two receptors and therefore, it is utilized in this study as a unique tool to illustrate the specific functions performed by SCTR/AT1aR heteromer. STM-II and ATM-4 are discovered as the interacting surfaces of SCTR/AT1aR heteromer, in which STM-II can only disrupt heteromer formation, while ATM-4 can inhibit both receptor homomer formation. Previous study shows that hyperosmolality-induced water drinking behaviour in mice is greatly suppressed after intracerebroventricular (i.c.v.) injection of STM-II and ATM-4 upon hyperosmotic shock, suggesting that this heteromer has an essential role in mediating water drinking behaviour on hyperosmotic stress. However, in vivo role of SCTR/AT1aR in central osmoregulatory centre is yet to be elucidated. Vasopressin (Vp) is one of the key components to access osmoregulation because of the physiological link between Vp release and drinking behaviour, meanwhile, ANGII and SCT are potent in stimulating Vp release, hence it is a spate of interest to understand whether SCTR/AT1aR heteromer regulate osmoregulation via Vp release pathway. In this study, we demonstrated that SCTR/AT1aR heteromer is involved in the regulation of Vp release and expression, as well as the central neural involvement in PVN. Upon SCT/ANGII-stimulation, plasma Vp release was largely reduced (47.64% decrease) and Vp expression in PVN is significantly dropped (64.08% decrease) 15 mins after i.c.v injection of STM-II or ATM-4. This finding supports the hypothesis of SCTR/AT1aR in mediating water balance, and also provides concrete basis in demonstrating the in vivo role of a GPCR heteromer.