G protein-coupled receptor 35, or GPR35, is a cellular receptor that receives signals from outside the cell and transmits them inward. GPR35 is found throughout the body and is involved in various biological processes. Its roles suggest importance in maintaining health and contributing to different disease states.
Understanding GPR35: A Key Receptor
GPR35 belongs to the G protein-coupled receptor (GPCR) family, the largest and most varied collection of membrane receptors involved in cellular communication. It is found in numerous tissues and cell types throughout the body, including immune cells, the gastrointestinal tract, and the nervous system. It is highly expressed in the small intestine and colon, with detectable levels also present in the stomach, liver, spleen, kidney, and sympathetic neurons.
GPR35 activates when specific molecules, known as ligands, bind to it. Kynurenic acid (KYNA), a tryptophan metabolite, is a notable endogenous ligand. Other proposed activators include lysophosphatidic acid (LPA) species and 5-hydroxyindoleacetic acid (5-HIAA). Ligand binding triggers a cascade of events inside the cell, often involving the activation of G proteins such as Gαi/o and Gα12/13. This activation can lead to changes in intracellular signaling pathways, like the inhibition of adenylate cyclase, a decrease in cyclic AMP levels, or effects on cell shape and motility through RhoA activation.
Physiological Functions of GPR35
GPR35 contributes to normal bodily functions and homeostasis across several systems. In the immune system, GPR35 modulates inflammatory responses. Its activation influences immune cell activity, potentially reducing inflammation and regulating cytokine production and chemotactic movements.
Within the gastrointestinal tract, GPR35 is involved in gut motility and maintaining intestinal barrier integrity. It also contributes to mucosal repair by promoting cell migration and proliferation in the colon. GPR35 acts as a sensor for bacterial toxins, initiating immune responses.
GPR35 also contributes to the body’s pain perception pathways. Activating GPR35 can reduce nociceptive pain. Its presence in neurons and ability to modulate cAMP production and inhibit N-type Ca2+ channels indicates its participation in pain management.
GPR35 has a role in metabolic regulation. It is expressed in the gastrointestinal tract and implicated in regulating energy homeostasis. GPR35 activation can influence lipid metabolism and thermogenesis in adipose tissue, potentially by increasing gene expression linked to these processes.
GPR35’s Involvement in Disease
Dysregulation of GPR35 is linked to various disease states, indicating its broader impact beyond normal physiological functions. In inflammatory diseases, GPR35’s involvement is complex, showing both pro-inflammatory and anti-inflammatory effects depending on the cellular context. Genetic variations in the GPR35 gene are associated with an increased risk of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In mouse models of IBD, GPR35 knockout mice exhibited reduced susceptibility to bowel inflammation, suggesting overactive GPR35 may promote disease progression.
GPR35 also plays a role in chronic pain conditions, distinct from its normal pain modulation. Its association with pain and sensory neurons, and its ability to influence cAMP production and N-type Ca2+ channels, suggests its involvement in conditions like neuropathic pain. Activation of GPR35 has been shown to reduce inflammatory pain.
In metabolic disorders, GPR35 is implicated in conditions such as obesity and type 2 diabetes. Studies show that genetic deletion of GPR35 in mice can lead to increased weight gain and glucose intolerance, particularly when on a high-fat diet. Activating GPR35 has been observed to suppress lipid accumulation in liver cells and promote lipid metabolism in adipose tissue, indicating its connection to these conditions.
Emerging research also links GPR35 to cancer progression. GPR35 expression is elevated in certain cancers, including gastric, colorectal, and non-small cell lung cancer. Higher GPR35 expression correlates with poorer patient outcomes and may promote tumor growth and metastasis by influencing angiogenesis and immune cell infiltration within the tumor microenvironment.
Targeting GPR35 for Treatment
The diverse roles of GPR35 in health and disease make it an appealing target for drug development. Scientists are actively developing compounds that can either activate (agonists) or block (antagonists) GPR35 to modulate its activity for therapeutic benefit. Synthetic agonists like zaprinast and pamoic acid have been identified and are used as research tools to explore GPR35’s biological functions.
Targeting GPR35 shows promise for new treatments across several disease areas. In inflammatory conditions like IBD, compounds that inhibit GPR35’s pro-inflammatory actions could be beneficial. Conversely, in contexts requiring inflammation, such as wound healing, augmenting GPR35’s anti-inflammatory effects might be advantageous. For pain relief, GPR35 agonists are being investigated for their potential to provide non-opioid analgesia, particularly for abdominal pain, by inhibiting the release of certain pain-transmitting substances.
In metabolic disorders, GPR35 agonists are being explored for their ability to influence energy homeostasis and improve insulin sensitivity, potentially offering new approaches for obesity and type 2 diabetes. While research is ongoing, and many compounds are still in preclinical stages, some GPR35-targeting drugs, such as Lodoxamide and sodium cromoglycate, have progressed to clinical trials for conditions like allergic conjunctivitis and idiopathic pulmonary fibrosis, respectively. This highlights the potential for GPR35-focused treatments to address a range of health concerns in the future.