Discover the fascinating connection between acidity, OGR1 receptors, and insulin regulation in pancreatic β-cells
Imagine your body as a sophisticated chemical laboratory, constantly monitoring subtle environmental changes to maintain perfect balance. Among the most carefully regulated parameters is pH - the measure of acidity or alkalinity - which fluctuates within microscopic ranges in different tissues. While we often think of blood sugar regulation in terms of carbohydrates and hormones, scientists have discovered a fascinating connection between acidity and insulin secretion that represents a breakthrough in our understanding of diabetes.
Your blood maintains a pH of approximately 7.4, but pancreatic tissues can experience localized pH fluctuations that influence insulin secretion.
At the heart of this discovery lies a remarkable protein called Ovarian Cancer G protein-coupled receptor 1 (OGR1), also known as GPR68. This molecular sensor detects subtle pH changes in your body and influences how pancreatic β-cells produce and release insulin. The implications of this discovery are profound, suggesting new therapeutic approaches for diabetes treatment by targeting these acid-sensing mechanisms 1 5 .
Our bodies maintain a blood pH of approximately 7.4, slightly alkaline, but this balance can shift in specific tissues under certain conditions. During inflammation, ischemia, or intense metabolic activity, tissues can become acidic—a change that cells must detect and address to maintain function.
For years, scientists believed that histidine residues on the extracellular portions of these receptors were solely responsible for pH detection. Hisitidine's molecular structure makes it particularly sensitive to pH changes, as its imidazole side chain can gain or lose protons within the physiological pH range.
However, recent groundbreaking research has revealed an additional mechanism: a triad of buried acidic residues (aspartic and glutamic acids) that form a unique structural feature in OGR1, GPR4, and GPR65. This triad, not found in other GPCRs, allows these receptors to detect subtle pH changes and transmit signals across the cell membrane 2 7 .
When extracellular pH drops (becomes more acidic), these residues undergo protonation (gain protons), triggering a conformational change in the receptor that activates intracellular signaling pathways.
OGR1 was initially discovered in connection with ovarian cancer (hence its name) but was later found to be widely expressed throughout the body, with particularly important functions in pancreatic β-cells. Research has shown that OGR1 is the predominant proton-sensing receptor in human pancreatic β-cells, where it plays a crucial role in both insulin secretion and β-cell differentiation 1 5 .
Unlike other proton-sensing GPCRs that primarily signal through the Gs-cAMP pathway, OGR1 mainly couples to Gq proteins, activating phospholipase C (PLC) and increasing intracellular calcium levels. This calcium signal then triggers insulin release from secretory granules 1 4 .
Fascinatingly, the expression of OGR1 in pancreatic β-cells is regulated by RFX6, a transcription factor essential for β-cell function and development. Studies using human β-cell lines (EndoC-βH2) and human islets have shown that when RFX6 levels decrease, OGR1 expression drops significantly—by approximately 60% in EndoC-βH2 cells and 42% in human islets 5 .
Figure 2: OGR1 expression reduction after RFX6 knockdown in different cell types 5
A pivotal study published in Scientific Reports in 2016 provided crucial insights into how human pancreatic β-cells respond to acidic conditions through GPR68 (OGR1). The research team used a comprehensive approach 5 :
| pH Condition | Exposure Time | Fold Change in IL-8 mRNA |
|---|---|---|
| pH 7.4 | 24 hours | 1.0 (baseline) |
| pH 6.8 | 24 hours | 3.2 |
| pH 6.6 | 24 hours | 5.7 |
| pH 6.4 | 24 hours | 8.9 |
| pH 6.4 | 8 hours | 4.3 |
| pH 6.4 | 48 hours | 12.5 |
Data adapted from 5
The experiment yielded several fascinating findings 5 :
Figure 3: IL-8 mRNA expression under different pH conditions over time 5
| Research Tool | Function/Application | Key Findings Using Tool |
|---|---|---|
| EndoC-βH2 Cell Line | Human β-cell model for in vitro studies | Confirmed GPR68 as primary β-cell pH sensor |
| YM-254890 | Selective Gq/11 inhibitor | Established Gq pathway involvement in pH sensing |
| siRNA for GPR68 | Gene silencing of OGR1 | Demonstrated OGR1's role in acid-induced responses |
| siRNA for RFX6 | Gene silencing of this transcription factor | Revealed RFX6-OGR1 regulatory axis |
| 3,5-Disubstituted Isoxazoles | OGR1 agonists | Shown to stimulate β-cell differentiation and insulin synthesis |
| Lorazepam | Positive allosteric modulator of OGR1 | Demonstrates pharmacological targeting potential |
The discovery of OGR1's role in insulin secretion has profound implications for understanding glucose homeostasis under both normal and disease conditions. Under physiological conditions, OGR1 may help fine-tune insulin secretion in response to metabolic changes that subtly affect local pH 1 4 .
In pathological conditions such as diabetic ketoacidosis—a serious complication of diabetes characterized by extremely acidic blood—OGR1 activation might contribute to both impaired insulin secretion and the inflammatory state that damages β-cells 5 .
Several approaches to targeting OGR1 therapeutically are emerging:
Compounds like 3,5-disubstituted isoxazoles could potentially enhance insulin secretion in type 2 diabetes patients.
Positive allosteric modulators could sensitize OGR1 to physiological pH changes.
Drugs that interrupt the link between OGR1 activation and inflammatory responses might protect β-cells.
Despite significant progress, important questions remain 5 8 :
The discovery of OGR1's role in insulin secretion adds a fascinating new dimension to our understanding of glucose metabolism—the pH dimension. This research reminds us that our bodies employ sophisticated multi-layered regulatory systems, with pH sensing joining more familiar regulators like hormones and nutrients.
As scientists continue to unravel the complexities of OGR1 and other proton-sensing receptors, we move closer to innovative therapies that could target these systems for diabetes treatment.
The story of OGR1 exemplifies how basic scientific research into seemingly obscure mechanisms—like how cells sense acidity—can yield unexpected insights into major diseases affecting millions worldwide.
The next time you enjoy a slightly sour taste, remember that your cells are also tasting their environment in a not-so-different way—and that this molecular tasting plays a crucial role in maintaining your metabolic health.