Central role of SCTR-AT1AR heterocomplex in modulating vasopressin release and expression within hypothalamus

Abstract

G-protein coupled receptor (GPCR), a major target of drug discovery nowadays, will be sometimes self-associate or form dimers and higher-order oligomers to elicit specific cellular responses. Although many sceptical speculations raise from the doctrine of GPCR oligomerization, there are still increasing numbers of studies indicating that oligomerization is a key factor in modulating GPCR function and signalling, and even constitute physiological implications in certain diseases. Previously our lab showed that angiotensin II type 1a receptor (AT1aR) and secretin receptor (SCTR) are able to form heteromer and involve in hyperosmolality-induced water drinking behaviour by utilizing transmembrane (TM) peptides, in which acting as competitors against the interacting surfaces between two receptors and become a unique approach to study specific GPCR oligomer functionality. STM-II and ATM-4 are discovered as the interacting surfaces of SCTR/AT1aR heteromer. Although previous study has revealed that hyperosmolality-induced water drinking behavior in mice is greatly suppressed after intracerebroventricular (i.c.v.) injection of STM-II and ATM-4 upon hyperosmotic shock, yet the in vivo role of SCTR/AT1aR in central osmoregulatory center is waiting for further investigation. Vasopressin (Vp) is one of the key components to access osmoregulation, 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. 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.