The role of receptor oligo-complex on blood pressure regulation through signaling modification

Abstract

Blood pressure is one of the most important physiological parameters that can affect the general well-being of an individual. As much as being tightly regulated in the body, it is also highly complex. Body water content and the resistance in the blood vessels are key players in affecting blood pressure. Therefore, many antihypertensive drugs available nowadays act on regulating these aspects by targeting G-protein-coupled receptors (GPCRs).

In terms of water homeostasis and vasoconstriction, the vasopressin receptors (AVPRs) are well established modulators, with AVPR2 governing water reabsorption in the kidney andAVPR1a mediating vasoconstriction. Parallel to the AVPRs, the secretin (SCT)/ secretin receptor (SCTR) axis is also involved in water homeostasis, with SCTR known to be co-expressed with AVPR1a to adjust renal blood flow. Considering the physiological relevance of the receptors, alongside the fact that GPCR oligomerization modulates receptor functioning, the role of receptor oligo-complex formation between SCTR and AVPR in controlling blood pressure is investigated. Using biophysical techniques to monitor receptor interactions, SCTR was confirmed to independently form oligo-complex with AVPR2 in a specific manner and, to a less extent, with AVPR1a. By measuring cellular signaling, the SCTR-AVPR2 complex was found to modulate both the cAMP and calcium signaling pathways. Applying the recently developed receptor transmembrane (TM) peptides to inhibit oligomer formation, the above-said phenomenon was confirmed to be uniquely due to the assembly of SCTR-AVPR2 complex. Furthermore, the complex was also able to rescue the trafficking of a mutated form of AVPR2 that causes nephrogenic diabetes insipidus (NDI). These findings in signaling modification and rescue of mutated receptor provide valuable information to enrich the current body of knowledge in water homeostasis; by establishing a relationship between SCTR, AVPR2 and NDI, it may pave the path for the design of future therapies to help patients suffering from the condition. For the SCTR-AVPR1a complex, signaling modification was seen in calcium signaling only, while in wire myograph experiments, blood vessels from SCT knockout mice showed variations in its contractility. Further investigation is necessary to unveil the cause behind these observations. Taking the two oligo-complexes together, this information could open up new possibilities in the field of hypertension research.