<table class="infobox infobox-gene">
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<th class="infobox-header" colspan="2">gpr89</th>
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<td class="label">Symbol</td>
<td><strong>GPR89</strong></td>
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<td class="label">Full Name</td>
<td>gpr89</td>
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<td class="label">Type</td>
<td>Gene</td>
</tr>
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<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=GPR89" target="_blank">Search NCBI</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
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<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">gpr89</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>GPR89</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>gpr89</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=GPR89" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
GPR89 (G Protein-Coupled Receptor 89), also known as GPRC5D (G Protein-Coupled Receptor Class C Group 5 Member D), is a member of the family C group of G protein-coupled receptors. The gene is located on chromosome 12p13.31 (NCBI Gene ID: 55527, Ensembl: ENSG00000166997, UniProt: Q9GZP0) and encodes a protein of 398 amino acids. Originally identified as a retinoic acid-inducible gene, GPR89 is primarily expressed in plasma cells and immune cells, where it functions as a calcium-sensing Gq-coupled receptor involved in immune cell function and calcium homeostasis. GPR89 has emerged as a highly validated therapeutic target in multiple myeloma, where it is overexpressed on malignant plasma cells. More recent research has revealed expression in neuronal cells and potential roles in neurodegenerative diseases, though these findings are less well-characterized. This review covers GPR89 gene structure, protein function, expression patterns, disease associations, therapeutic implications, and emerging research on potential roles in neurodegeneration. The protein represents an interesting case of a receptor with both immune and potentially neural functions, raising important questions about its physiological roles and therapeutic targeting. [@chen2015][@atamaniuk2010]
The GPR89 gene spans approximately 18 kb on chromosome 12p13.31 and encodes a 398-amino acid protein. The gene consists of multiple exons that encode the characteristic seven-transmembrane domain structure of G protein-coupled receptors. The promoter region contains retinoic acid response elements, explaining the retinoic acid-inducible nature of GPR89 expression. The gene shows relatively restricted expression compared to many other GPCRs, with highest expression in plasma cells and lower expression in various tissues including the brain. The genomic structure includes several polymorphic variants that have been associated with different phenotypes in population studies. The evolutionary history of GPR89 involves duplication events that gave rise to the GPRC5 family (GPRC5A-E), with GPR89 representing the D member of this family. Understanding the genomic organization provides insight into the regulation and evolution of this receptor. The chromosomal location of GPR89, 12p13.31, is not within a region commonly involved in copy number alterations in cancer, though specific variants may affect expression. [@chen2015]
GPR89 exhibits a distinctive tissue expression pattern with highest levels in plasma cells and certain immune populations. In the immune system, GPR89 is expressed at high levels in terminally differentiated B cells (plasma cells), where it represents one of the most highly expressed surface proteins. This high plasma cell expression makes it an attractive therapeutic target in multiple myeloma, a plasma cell malignancy. GPR89 is also expressed in some T cell populations and natural killer cells, though at lower levels than in plasma cells. Outside the immune system, GPR89 shows lower but detectable expression in several tissues, including the brain. In the central nervous system, GPR89 expression has been detected in neurons of the cortex, hippocampus, and cerebellum, as well as in astrocytes and microglia. The functional significance of neuronal GPR89 expression remains an active area of investigation. Peripheral tissues show variable expression, with higher levels in some endocrine tissues and lower levels in most other organs. The restricted expression pattern of GPR89 makes it an attractive target for selective therapies, particularly in multiple myeloma. [@smith2016]
GPR89 (GPRC5D) shares the seven-transmembrane domain architecture characteristic of G protein-coupled receptors in the family C group. Like other family C receptors, GPR89 has a large extracellular N-terminal domain that contains a Venus flytrap (VFT) module responsible for ligand binding. The protein is predicted to have seven transmembrane helices connected by three extracellular loops and three intracellular loops, with a C-terminal cytoplasmic tail. Unlike metabotropic glutamate receptors (the prototypical family C receptors), GPR89 does not appear to respond to glutamate or other classical family C ligands. Instead, GPR89 functions as a calcium-sensing receptor, with the extracellular domain detecting changes in extracellular calcium concentrations. This calcium-sensing function links GPR89 to cellular calcium homeostasis and downstream signaling cascades. The protein forms homodimers at the cell surface, a feature shared with other family C GPCRs that is important for function. Post-translational modifications including glycosylation in the extracellular domain and potential phosphorylation in the intracellular loops modulate receptor function. [@martinez2020]
GPR89 couples primarily to Gq proteins, leading to activation of phospholipase C (PLC) and generation of inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors on the endoplasmic reticulum, triggering calcium release from intracellular stores. DAG activates protein kinase C (PKC), which can phosphorylate numerous downstream targets. This Gq-coupled calcium signaling pathway is the primary signaling mechanism for GPR89 in most cell types. In some contexts, GPR89 may also couple to Gi/o proteins, leading to inhibition of adenylate cyclase and reduction in cAMP levels, though this coupling appears to be less prominent. The downstream consequences of GPR89 activation include changes in intracellular calcium levels, activation of PKC, and subsequent effects on gene expression, cell survival, and function. In plasma cells, GPR89 signaling may affect immunoglobulin production, cell survival, and migration. In neurons, GPR89-mediated calcium signaling could influence neuronal excitability, synaptic function, and cellular stress responses. The specifics of GPR89 signaling depend on the cell type and context. @martinez2020
GPR89 is highly expressed in plasma cells, the terminally differentiated B cells responsible for antibody production. In normal plasma cells, GPR89 likely plays roles in calcium homeostasis and cell survival, though the precise physiological functions remain incompletely characterized. The high expression of GPR89 on plasma cells suggests it may be involved in the differentiation or maintenance of plasma cells. Studies have shown that GPR89 expression increases as B cells differentiate into plasma cells, making it a marker of terminal B cell differentiation. The calcium-sensing function of GPR89 may allow plasma cells to respond to changes in the bone marrow microenvironment, where calcium levels fluctuate in association with bone remodeling. Additionally, GPR89 signaling may influence antibody secretion, as calcium is involved in the secretory pathway. Understanding the normal functions of GPR89 in plasma cells provides context for its role in plasma cell malignancies and its utility as a therapeutic target. [@yang2017]
GPR89 has emerged as one of the most important therapeutic targets in multiple myeloma, a plasma cell malignancy characterized by clonal proliferation of malignant plasma cells. GPR89 is expressed at very high levels on malignant plasma cells in most patients with multiple myeloma, making it an ideal target for antibody-based therapies. The expression of GPR89 on multiple myeloma cells is even higher than on normal plasma cells, providing a therapeutic window. Several therapeutic approaches targeting GPR89 are in development and clinical testing. T cell-engaging bispecific antibodies that bind both GPR89 on myeloma cells and CD3 on T cells have shown promising results in early clinical trials, inducing remission in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T cells targeting GPR89 have also shown efficacy in preclinical models and early clinical studies. The main toxicity concern with GPR89-targeted therapies is on-target off-tumor toxicity against normal plasma cells, leading to hypogammaglobulinemia, but this is manageable with intravenous immunoglobulin replacement. GPR89 represents a promising new target for multiple myeloma therapy. [@chanankhan2018]
The potential role of GPR89 in Alzheimer's disease (AD) is an emerging area of investigation with preliminary findings suggesting possible involvement. Calcium dysregulation is a well-established feature of AD, with pathological changes in intracellular calcium contributing to synaptic dysfunction, tau pathology, and neuronal death. As a calcium-sensing receptor, GPR89 could potentially be affected by or contribute to calcium dysregulation in AD. Studies have detected GPR89 expression in neurons and glia in brain regions relevant to AD, including the hippocampus and cortex. One study reported altered GPR89 expression in AD brain tissue compared to controls, though these findings require confirmation. The mechanisms by which GPR89 might contribute to AD pathogenesis could include effects on neuronal calcium homeostasis, neuroinflammation (given the immune cell functions of GPR89), or synaptic function. However, the evidence for GPR89 involvement in AD remains preliminary, and more research is needed to establish whether GPR89 plays a significant role in AD pathogenesis. The potential for targeting GPR89 in AD is even more speculative at this stage. [@cohen2021]
GPR89 may also have potential relevance to Parkinson's disease (PD), though evidence is similarly limited. Dopaminergic neurons of the substantia nigra pars compacta, which degenerate in PD, are exposed to complex calcium signaling requirements due to their autonomous pacemaking activity. Calcium dysregulation is implicated in dopaminergic neuron vulnerability in PD, making calcium-related proteins of interest. GPR89 expression has been detected in some dopaminergic neurons, though the functional significance is unclear. One study suggested potential involvement of GPR89 in PD based on expression analysis, but direct evidence linking GPR89 to PD pathogenesis is lacking. Like in AD, more research is needed to determine whether GPR89 plays any role in PD. The expression of GPR89 in microglia, which are activated in PD and contribute to neuroinflammation, could also be relevant if GPR89 affects microglial function in ways that influence dopaminergic neuron survival. Overall, the potential role of GPR89 in PD remains an open question requiring further investigation. @cohen2021
GPR89 may have potential relevance to other neurodegenerative conditions beyond AD and PD. One preliminary study mentioned potential involvement in amyotrophic lateral sclerosis (ALS), though the evidence is very limited. Given the expression of GPR89 in some neuronal populations and its calcium-sensing function, it could potentially influence neuronal survival in various disease contexts. The immune functions of GPR89 could also be relevant to neuroinflammation, which is a feature of many neurodegenerative diseases. Microglial GPR89 could potentially modulate inflammatory responses in the CNS. However, these possibilities remain speculative and require experimental validation. The study of GPR89 in neurodegeneration is at an early stage, and much remains to be learned about its expression, function, and potential disease relevance in the nervous system. @johnson2019
The therapeutic targeting of GPR89 in multiple myeloma represents one of the most advanced applications of GPCR-targeted therapy in cancer. Several therapeutic modalities are being developed and tested in clinical trials. Bispecific antibodies that engage T cells to kill GPR89-expressing myeloma cells have shown remarkable efficacy in early-phase trials, with high response rates even in patients who had failed multiple prior lines of therapy. These antibodies typically bind GPR89 with one arm and CD3 with the other, forming an immunologic synapse that activates T cells against the myeloma cells. CAR T cells engineered to recognize GPR89 have also shown promise, with complete responses observed in some patients. The main challenge is managing on-target off-tumor toxicity against normal plasma cells, which also express GPR89. This leads to loss of normal antibody production (hypogammaglobulinemia), which can be managed with immunoglobulin replacement therapy. Future directions include combination strategies, dual-targeting approaches to prevent antigen escape, and optimization of dosing and scheduling. @choi2022
The therapeutic potential of GPR89 modulation in neurodegenerative diseases is far less advanced than in multiple myeloma. If future research confirms that GPR89 plays a significant role in AD, PD, or other neurodegenerative conditions, targeting it could represent a novel therapeutic approach. The calcium-sensing function of GPR89 makes it potentially amenable to small molecule modulation. Agonists that enhance GPR89 signaling could potentially normalize calcium homeostasis in neurons, while antagonists could potentially reduce pathological calcium signaling. However, the development of such therapies would require a much better understanding of GPR89's normal functions in the brain and its role in disease pathogenesis. The expression of GPR89 on immune cells also raises the possibility of targeting neuroinflammation through GPR89 modulation. Given the preliminary nature of the evidence for GPR89 involvement in neurodegeneration, it is too early to speculate about specific therapeutic approaches. Basic research on GPR89 in the nervous system is needed before translation to therapy can be considered.
Significant questions remain about GPR89 function and disease relevance. In the immune system, the physiological ligand of GPR89 and its normal functions in plasma cells require further clarification. The downstream signaling networks and biological functions of GPR89 in different cell types need systematic characterization. In the nervous system, the expression patterns, cellular localization, and functions of GPR89 are poorly understood. The potential roles of GPR89 in neurodegeneration need to be rigorously tested using appropriate model systems. The relationship between GPR89 expression and disease outcomes requires investigation in large clinical cohorts. Better tools for studying GPR89, including selective antibodies, small molecule modulators, and genetic models, would facilitate progress.
New research approaches are beginning to address the knowledge gaps in GPR89 biology. Single-cell transcriptomics is revealing GPR89 expression across different immune and neuronal cell types. Structural studies are providing insight into GPR89's ligand-binding properties and mechanism of activation. Patient-derived models of multiple myeloma are enabling study of GPR89 as a therapeutic target. Induced pluripotent stem cell models of neurons may allow investigation of GPR89 in neurodegeneration. These emerging approaches promise to advance understanding of GPR89 biology and its therapeutic potential.