Structure and Signalling of Secretin Receptor in Water and Blood Pressure Control

Abstract

Secretin receptor (SCTR), a prototypic class B G-protein coupled receptor (GPCR) known to be involved in many crucial physiological functions. Along with SCTR involvement in other physiological function, our group has also explored the role of SCTR as an important regulator of body fluid homeostasis. Through homology modeling and virtual docking experiments, a SCTR 3D model by was generated to understand the binding of SCT peptide onto SCTR. To consolidate the model and to locate the binding domain, 19 analogs of SCT peptide were used in the binding study and together with previous photoaffinity labeling experiments, we have developed an SCTR model in complex with SCT peptide. In addition, we found that SCT/SCTR are substantially expressed along the central osmoregulatory axis and regulate water. drinking behavior whenever the body cells experience osmotic stress. Upon hyperosmolality condition, SCT/SCTR will be stimulated in hypothalamus and act as a neurohypophysial factor to trigger the release of antidiuretic hormone, vasopressin, from pituitary gland, further activating the process of water reabsorption in kidney. In addition, SCT/SCTR was found to mediate water drinking behavior together with angiotensin II (ANGII) in brain during hyperosmotic stress. More importantly, SCT/SCTR axis is discovered to be a key factor in ANGII-mediated osmoregulation where SCTR and angiotensin II type 1a receptor (AT1aR) can form heteromer in hypothalamus and perform specific osmoregulatory actions. SCT has also been observed to have short term promoting action on heart and blood vessels where SCT infusion increases blood flow in arteries and dilates arterioles. Aside its wide expression in brain related to osmoregulation, SCT/SCTR generally expressed in critical organs including brain, heart and kidneys where more constant blood pressure is desirable. Previously, our lab has found that SCT deficiency led to detrimental effect on the cardiovascular and pulmonary system. In SCT-/- mice, right ventricular systolic pressure (RVSP), pulmonary acceleration time (PAT) and pulmonary ejection time (PET) were found to be continuously and significantly increased, where these parameters are the important index for pulmonary hypertension therefore it provides evidence that SCT deficiency will cause pulmonary arterial hypertension. Additionally, from the histochemical staining, the pulmonary arterial walls were found to be remarkably thicker and perivascular fibrosis was observed in SCT-/- mice, demonstrating that lack of SCT causes pulmonary hypertension. Adverse effect on the cardiovascular system was also shown from the increase of systemic arterial pressure and hypertrophy in right ventricle of SCT-/- mice’s hearts. With the indication of its role in blood pressure control, SCT replacement therapy has emerged as a new approach on hypertension. Our lab has shown that SCT replacement would revert all the pathological and behavioral changes, suggesting that 1) SCT has a modulatory role in blood pressure control, 2) adverse effect in cardiovascular and pulmonary system is reversible by SCT replacement therapy.