Key Takeaways & Executive Findings
- •• Identified four iGluR subunits in lampreys, including Lr-GRIK1, and confirmed their conserved structural features with jawed vertebrates. • Lr-GRIK1 is highly expressed in kidney tissue, suggesting a role beyond neurotransmission. • Silencing Lr-GRIK1 in lampreys altered expression of genes involved in immune response pathways, indicating a negative regulatory role in immunity. • This study provides the first functional evidence of KARs in jawless vertebrates, expanding understanding of iGluR evolution and immune function.
Abstract
Kainate receptors (KARs) are one of the ionotropic glutamate receptor (iGluR) families, and their antagonists are being investigated for the treatment of several neurological disorders, including Alzheimer’s disease, a neurodegenerative condition, etc. As early as 1990, Bettler et al. [1] first cloned the GRIK1 subunit of KARs, marking a pivotal advancement in understanding these receptors. Members of the iGluR family have been identified in other jawed vertebrates and exhibit conserved structural features. However, research into iGluRs in jawless vertebrates has been limited. Owing to the unique evolutionary position of lampreys, their iGluRs might also present functions distinct from those of jawed vertebrates; therefore, it is particularly important to study iGluRs in lampreys. In this study, we identified four homologous subunits of iGluRs in lampreys, including Lr-GRIA2, Lr-GRIA4, Lr-GRIK1 and Lr-GRIN2B. Lampreys occupy a unique evolutionary position, making phylogenetic analysis of iGluR subunits between lampreys and other species essential for understanding iGluR evolution. Given the distinctive functional characteristics of iGluR family members, particularly KAR subtypes, we focused on the functional validation of Lr-GRIK1. First, we confirmed the expression of Lr-GRIK1 in lampreys and examined its expression profiles across various tissues via qPCR and western blotting. To elucidate the functional role of Lr-GRIK1 in lampreys, we used an siRNA to silence Lr-GRIK1. We subsequently conducted transcriptome sequencing of both the silenced and control groups to construct and analyze their expression profiles. Our analysis revealed differential expression of genes enriched in pathways related to signal transduction and the immune system, highlighting potential roles of Lr-GRIK1 beyond traditional neurotransmission functions. Unlike in jawed vertebrates, transcriptome enrichment provides a new direction for understanding the function of Lr-GRIK1. Therefore, we monitored the changes in Lr-GRIK1 expression in the kidney tissue of lampreys after stimulation. In addition, we confirmed that Lr-GRIK1 affects the expression levels of immune-related molecules during the immune response process. These findings provide insights into the broader functional significance of Lr-GRIK1 in the biology of lampreys.
1. Introduction
Kainate receptors (KARs) are one of the ionotropic glutamate receptor (iGluR) families, and their antagonists are being investigated for the treatment of several neurological disorders, including Alzheimer’s disease, a neurodegenerative condition, etc. As early as 1990, Bettler et al. [1] first cloned the GRIK1 subunit of KARs, marking a pivotal advancement in understanding these receptors. Members of the iGluR family have been identified in other jawed vertebrates and exhibit conserved structural features. However, research into iGluRs in jawless vertebrates has been limited.
Owing to the unique evolutionary position of lampreys, their iGluRs might also present functions distinct from those of jawed vertebrates; therefore, it is particularly important to study iGluRs in lampreys. In this study, we identified four homologous subunits of iGluRs in lampreys, including Lr-GRIA2, Lr-GRIA4, Lr-GRIK1 and Lr-GRIN2B. Lampreys occupy a unique evolutionary position, making phylogenetic analysis of iGluR subunits between lampreys and other species essential for understanding iGluR evolution.
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Ruyu Zhuang, Zihao Yan, Shuyuan Zhang, Meixuan Li, Feng Sun, Ya Pang, Ding Li, Liang Zhao, Yinglun Han (2026). KARs negatively regulate the immune response in lamprey. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025094
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Frequently Asked Questions
What are kainate receptors (KARs) and why are they important?
KARs are a family of ionotropic glutamate receptors that mediate fast synaptic transmission in the central nervous system. They are implicated in various neurological disorders, making them targets for therapeutic intervention.
What is the significance of studying iGluRs in lampreys?
Lampreys are jawless vertebrates that occupy a unique evolutionary position. Studying their iGluRs provides insights into the evolution of these receptors and may reveal functions distinct from those in jawed vertebrates, including potential roles in immune regulation.
How was Lr-GRIK1 silenced in lampreys?
Lr-GRIK1 was silenced using small interfering RNA (siRNA) administered via intraperitoneal injection. The efficiency of silencing was validated by qPCR in kidney tissue, which showed the highest expression of Lr-GRIK1.
What were the main findings regarding Lr-GRIK1 and immune response?
Silencing Lr-GRIK1 led to differential expression of genes involved in immune-related pathways, suggesting that Lr-GRIK1 negatively regulates the immune response in lampreys. This is a novel function not previously attributed to KARs.
What are the potential implications of this research?
This research expands the understanding of KAR functions beyond neurotransmission, highlighting their role in immune regulation. It may also inform evolutionary studies of the immune system and provide a basis for developing novel therapeutic strategies targeting KARs in immune-related conditions.
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