GRIK2

GRIK2 (Glutamate Ionotropic Receptor Kainate Type Subunit 2) is a protein-coding gene located on the human chromosome 6q16.3 q21. The GRIK2 gene encodes a subunit of the alginate glutamate receptor. The gene product belongs to the alginate receptor family of glutamate receptors (KAR), which has five kainate receptor subunits, GRIK1, GRIK2, GRIK3, GRIK4, and GRIK5. KAR subunits can form a tetramer functional channel, either through GRIK1, GRIK2 or GRIK3 to form a homologous complex channel, and can also bind to each other heterologously or with GRIK4 or GRIK5 subunits. This channel functions as a ligand-activated ion channel. Studies have found that glutamate receptors are the main excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiological processes. The KAR subunit GRIK2 is mainly expressed in the hippocampus, basal ganglia and cerebellum. KARs containing GRIK2 subunits are mainly located in excitatory neurons. They regulate the release of glutamate before and after synapses, thereby supporting the transmission of excitability in the synapses. The subunits encoded by the gene undergo RNA editing at multiple sites in the first and second transmembrane domains, which scientists believe will change the structure and function of the receptor complex. Currently, splicing and transcription variants of this gene encoding different isoforms have been described.

Figure 1. Schematic showing the pre- and postsynaptic arrangement for kainate receptors at the mossy fibre-CA3 contact. (Lerma, Juan et al.; 2003)

It is well known that L-glutamate acts as an excitatory neurotransmitter in many synapses in the central nervous system. The combination of glutamate receptors and the excitatory neurotransmitter L-glutamate will cause a conformational change, leading to the opening of cation channels, thereby converting chemical signals into electrical impulses. The receptor then rapidly desensitizes and enters a transient state of inactivation, which is characterized by the presence of a bound agonist.

Functions of GRIK2

Similar to other glutamate receptors, GRIK2 also plays an important and unique role in mediating excitatory neurotransmission in the brain. Clinical studies have found that this receptor may play a role in synaptic plasticity and has important functions for learning and memory. It is also involved in the transmission of light information from the retina to the hypothalamus. GRIK2 has been found to be related to different human diseases. In animal models, it has been reported that GRIK2-deficient mice are resistant to neuronal degeneration and seizures induced by alginic acid, and GRIK2 knockdown can prevent neuronal loss after ischemia in the hippocampal CA1 area of rats.

GRIK2 and Disease

The results of clinical studies have shown that mutations in the GRIK2 gene are related to autosomal recessive cognitive impairment. The disease associated with GRIK2 is autosomal recessive non-syndromic mental retardation.

Non-syndromic Mental Retardation

Non-syndromic mental retardation is one of the most important unresolved issues in genetic health care. The study found that a complex mutation in GRIK2 is associated with moderate to severe non-syndromic autosomal recessive low intelligence in a large Iranian family of close relatives. The predicted GRIK2 gene product lacks the first ligand-binding domain, the adjacent transmembrane domain and the putative pore ring, indicating the complete loss of GRIK2 protein function, which is supported by electrophysiological data.

References

1. Motazacker MM, et al.; A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am. J. Hum. Genet. 2007, 81 (4): 792-8.
2. Paschen W, et al.; Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment. Genomics. 1994, 20 (3): 435-40.
3. Lerma, Juan et al.; Roles and rules of kainate receptors in synaptic transmission. Nature Reviews Neuroscience. 2003, 4(6), 481-495.