Scientists have identified this receptor in brain mural cells that regulates reperfusion injury.

Optimal pH homeostasis for cellular functions is maintained by acid-base balance through multiple buffering systems, reminiscent of the bicarbonate system, throughout the cell. Changes on this balance could have implications for health, prompting a more in-depth take a look at how cells respond under pathological conditions. Although previous research has provided recent information, several points remain unexplored. Researchers in Japan have now discovered a recent bicarbonate-sensing receptor that regulates ischemic reperfusion injury and provides therapeutic insight into the treatment of ischemic stroke.

Cells actively depend on maintaining an appropriate acid-base balance to support optimal functioning. Under normal physiological conditions, the pH inside cells stays inside a controlled range. Nonetheless, disruptions to this balance have been linked to a wide selection of health conditions, each minor and catastrophic. Changes within the extracellular environment are monitored by “membrane receptors”, of which G protein-coupled receptors (GPCRs) are a big family of membrane proteins that mediate many cellular responses. Nonetheless, the role of GPR30, also often called G-protein-coupled estrogen receptor or estrogen membrane receptor, and its importance in cellular responses to acid-base disturbances remain unclear.

In a groundbreaking study, a team of scientists from Juntendo University in Japan, led by specially appointed Associate Professor Airi Jo-Watanabe, examined cellular responses to pH changes, with a selected give attention to exploring the importance of GPR30. The study was recently published in Nature communication February 27, 2024, and co-authored by Dr. Takehiko Yokomizo, Dr. Nobutaka Hattori, and Dr. Takahiro Osada. This study represents a key step in understanding the mechanisms that govern cellular behavior in response to changes in bicarbonate concentration. Sharing the study’s findings, Dr. Jo-Watanabe explains: “Our goal was to discover a GPCR related to acid-base balance, and while looking for targets, GPR30 caught our attention. We identified GPR30 as a bicarbonate-sensing GPCR after which focused on determining its contribution to the pathophysiology of ischemic stroke.

So why did scientists select GPR30 for his or her study? While browsing the Psychoactive Drug Screening Program (PDSP) database, the team got here across 10 GPCRs that were expressed mainly within the stomach and pancreas, 4 of which were highly expressed within the brain. Because pathological conditions reminiscent of ischemia and reperfusion can disrupt the acid-base balance by affecting vascular and perivascular cells via receptors, researchers looked for GPCRs highly expressed within the cerebral microcirculation and identified Gpr30 as one in every of them. This aroused curiosity concerning the role of GPR30 as a possible acid-base sensor within the brain. The team found that removing bicarbonate from the culture medium reduced GPR30 activation (calcium responses) in GPR30-overexpressing MCF-7 and HEK cells, indicating that bicarbonate prompts GPR30 in vitro.

The mouse myoblast cell line C2C12 was used to verify that endogenous GPR30 is activated by bicarbonate ions in vitro. This has been further confirmed ex vivo using GPR30 knock-in mice expressing a fluorescent reporter “Venus.” Confocal microscopy revealed strong GPR30 expression within the brain microcirculation, particularly in pericytes, cells that help maintain homeostatic and hemostatic functions within the brain. This indicated a possible mechanism for the role of GPR30 in cerebrovascular regulation.

They then set out to analyze the role of GPR30 in cerebral ischemia-reperfusion injury (interruption and restoration of blood flow to tissues, causing cellular dysfunction), which is central to the pathophysiology of ischemic stroke. GPR30 deficiency was then examined within the context of ischemia-reperfusion injury, and researchers observed that GPR30-deficient mice exhibited significant protection against this injury, exhibiting reduced neurological deficits, blood-brain barrier disruption, and cell death by apoptosis. Furthermore, GPR30 deficiency led to improved blood flow after ischemia-reperfusion injury, highlighting its role in controlling blood flow in each large vessels and capillaries.

The bicarbonate buffer system delivers bicarbonate ions and protons to the acid/base sensing GPCR identified on this study, modulating signal transduction at the side of the consistently changing extracellular environment. The unexpected association between GPR30 and bicarbonate detection encourages further research into the mechanisms governing cerebrovascular health, offering a possible opportunity to develop targeted strategies to mitigate the consequences of ischemic stroke reperfusion injury. Dr. Jo-Watanabe concludes by saying, “Our findings pave the best way for a revolutionary approach to modulating vascular reactivity to support overall health by fine-tuning homeostatic vascular reactivity via the bicarbonate receptor.“

Taken together, these studies may represent a paradigm shift in our understanding of the role of receptors in cerebrovascular regulation.