Dysregulation of GPCRs
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- Recombinant Proteins
- Native Proteins
- GMP Proteins
- Fluorescent Dyes
- Dysregulation of GPCRs Information
- GPCRs Class A
- GPCRs Class B
- GPCRs Class C
- GPCRs Class F
- GPCRs Taste/Vomeronasal Receptors
- Physiological Functions of GPCRs
- How Do GPCRs Work?
- Dysregulation of GPCRs
- GPCRs Desensitization
- GPCRs Diseases
- G-protein coupled receptor (GPCR) pathways
- GPCRs Subfamily
- G-protein Signaling
Ligands/receptors proteins
Interacting Proteins
Inhibitors/promotors
Substrate
Class A rhodopsin-like
Class B secretin-like
Metabotropic glutamate/pheromone
Class F frizzled (FZD)
Other GPCRs
The physiological functions of cells and tissues triggered by various stimuli are orchestrated by GPCRs, the building blocks of homeostasis. However, dysregulation of GPCR signaling can cause a variety of diseases, highlighting their importance in pathophysiology.
Cancer
GPCRs have been recognized as a critical part of cancer development and progression. When GPCRs are abnormally activated, it can lead to increased cell proliferation, migration and survival, causing tumors to grow and spread. For example, the vasopressin receptor has been implicated in the growth of some types of cancer cells. Then there are chemokine receptors, such as CXCR4, which play a role in the spread of breast cancer and other cancers. These receptors don't just help cancer cells move around; they also create a supportive environment for tumors to grow by affecting blood vessel formation and inflammation.
Fig. 1: Function of GPCRs in cancer. GPCRs play key roles in promoting tumor growth, angiogenesis, metastasis, and immune evasion. Tumor-released GPCR agonists stimulate angiogenesis by activating GPCRs on endothelial cells. These receptors also mediate communication between tumor cells, stromal cells, blood vessels, and immune cells, as well as responding to neurotransmitters from tumor-induced nerve growth. GPCRs on tumor cells aid in the migration and spread of cancer cells to distant organs, enhancing metastasis
(Wu et al., 2019).
Mutations in GPCRs themselves can lead to altered signaling pathways that support oncogenic processes. A notable case is the mutation of beta-adrenergic receptors (βARs), where aberrant signaling can enhance the survival and proliferation of malignant cells. In addition, GPCRs can interact with other oncogenic signaling pathways, contributing to a more complex network of signaling that drives tumorigenesis. This interconnectivity between GPCR signaling and other pathways makes them valuable therapeutic targets for anticancer drugs.
GPCRs related to cancer:
Cardiovascular Diseases
In the cardiovascular system, blood pressure and arterial tone. Unregulated GPCR signaling is responsible for the major cardiovascular disorders, including hypertension, heart failure and atherosclerosis. For example, the angiotensin II type 1 receptor (AT1R) regulates blood pressure and fluid levels. Overactivation of the AT1R is associated with increased vasoconstriction, sodium retention and ultimately hypertension. In contrast, β-adrenergic receptors control how the heart responds to sympathetic impulses, and dysfunction causes heart failure.
During heart failure, alterations in GPCR signaling can alter cardiac contractility and stress response. Abnormal GPCR signaling can lead to maladaptive remodeling of the heart, exacerbating the disease. Furthermore, GPCRs contribute to the development of atherosclerosis, in which chemokine receptor-dependent inflammatory responses drive plaque formation and fragility. Thus, GPCR targets represent an exciting opportunity for new therapeutic approaches to treat cardiovascular disease.
GPCRs related to cardiovascular diseases:
Neurological Disorders
GPCRs are vital in neurotransmitter signaling, and their dysfunction is implicated in a range of neurological and psychiatric disorders. For example, the dopamine receptors, which are GPCRs, are crucial in the pathophysiology of schizophrenia and Parkinson's disease. In schizophrenia, alterations in dopamine signaling, particularly through the D2 receptor, are associated with psychotic symptoms. Similarly, the serotonin receptors (5-HT receptors) play significant roles in mood regulation, with dysregulation contributing to depression and anxiety disorders.
In neurodegenerative diseases such as Alzheimer’s, GPCRs are involved in signaling pathways that regulate synaptic plasticity and cognitive function. For example, alterations in muscarinic acetylcholine receptors can impair cholinergic signaling, which is essential for learning and memory. In addition, the involvement of GPCRs in neuroinflammation suggests their role in the progression of these disorders, highlighting the need for targeted therapies that can modulate GPCR activity.
Fig. 2: Orphan GPCRs in Neurodegenerative Disorders. The figure illustrates the expression and localization of orphan GPCRs in Parkinson’s Disease, Alzheimer’s Disease, Multiple Sclerosis, and Huntington Disease (Öz-Arslan et al. , 2024).
GPCRs related to neurological disorders:
Metabolic Conditions
GPCRs also have a significant role in metabolic regulation, influencing energy balance, glucose metabolism, and lipid homeostasis. The glucagon-like peptide-1 receptor ( GLP1R ) is an example of a GPCR involved in glucose homeostasis and insulin secretion. Dysregulation of GLP-1 signaling is implicated in the development of type 2 diabetes and obesity. Additionally, GPCRs such as the beta-adrenergic receptors influence lipolysis and thermogenesis in adipose tissue, affecting body weight regulation.
The relationship between GPCRs and metabolic syndrome is complex, with different GPCRs involved in appetite regulation, insulin sensitivity, and fat distribution. The FFAR1 receptor, which is activated by free fatty acids, plays a critical role in metabolic signaling and has implications for insulin sensitivity. Targeting GPCRs that influence metabolic pathways represents a therapeutic avenue for the treatment of obesity and diabetes and their associated complications.
GPCRs related to metabolic conditions:
Reference
- Öz-Arslan, D., Yavuz, M., & Kan, B. (2024). Exploring orphan GPCRs in neurodegenerative diseases. Frontiers in Pharmacology , 15 .
Wu, V., Yeerna, H., Nohata, N., Chiou, J., Harismendy, O., Raimondi, F., Inoue, A., Russell, R. B., Tamayo, P., & Gutkind, J. S. (2019). Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy. Journal of Biological Chemistry , 294(29), 11062–11086.