GRIN1

Official Full Name

glutamate ionotropic receptor NMDA type subunit 1

Organism

Homo sapiens

GeneID

2902

Background

The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

Synonyms

NR1; MRD8; hNR1; GluN1; NMDA1; DEE101; NDHMSD; NDHMSR; NMD-R1; NMDAR1;

Bio Chemical Class

Glutamate-gated ion channel

Protein Sequence

MSTMRLLTLALLFSCSVARAACDPKIVNIGAVLSTRKHEQMFREAVNQANKRHGSWKIQLNATSVTHKPNAIQMALSVCEDLISSQVYAILVSHPPTPNDHFTPTPVSYTAGFYRIPVLGLTTRMSIYSDKSIHLSFLRTVPPYSHQSSVWFEMMRVYSWNHIILLVSDDHEGRAAQKRLETLLEERESKAEKVLQFDPGTKNVTALLMEAKELEARVIILSASEDDAATVYRAAAMLNMTGSGYVWLVGEREISGNALRYAPDGILGLQLINGKNESAHISDAVGVVAQAVHELLEKENITDPPRGCVGNTNIWKTGPLFKRVLMSSKYADGVTGRVEFNEDGDRKFANYSIMNLQNRKLVQVGIYNGTHVIPNDRKIIWPGGETEKPRGYQMSTRLKIVTIHQEPFVYVKPTLSDGTCKEEFTVNGDPVKKVICTGPNDTSPGSPRHTVPQCCYGFCIDLLIKLARTMNFTYEVHLVADGKFGTQERVNNSNKKEWNGMMGELLSGQADMIVAPLTINNERAQYIEFSKPFKYQGLTILVKKEIPRSTLDSFMQPFQSTLWLLVGLSVHVVAVMLYLLDRFSPFGRFKVNSEEEEEDALTLSSAMWFSWGVLLNSGIGEGAPRSFSARILGMVWAGFAMIIVASYTANLAAFLVLDRPEERITGINDPRLRNPSDKFIYATVKQSSVDIYFRRQVELSTMYRHMEKHNYESAAEAIQAVRDNKLHAFIWDSAVLEFEASQKCDLVTTGELFFRSGFGIGMRKDSPWKQNVSLSILKSHENGFMEDLDKTWVRYQECDSRSNAPATLTFENMAGVFMLVAGGIVAGIFLIFIEIAYKRHKDARRKQMQLAFAAVNVWRKNLQDRKSGRAEPDPKKKATFRAITSTLASSFKRRRSSKDTSTGGGRGALQNQKDTVLPRRAIEREEGQLQLCSRHRES

Open

Disease

Alzheimer disease, Bacterial infection, Cerebral ischaemia, Dissociative neurological symptom disorder, Epilepsy/seizure, HIV-infected patients with tuberculosis, Multiple sclerosis, Neurodegenerative disorder, Obsessive-compulsive disorder

Approved Drug

1 +

Clinical Trial Drug

3 +

Discontinued Drug

12 +

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Detailed Information

The GRIN1 gene plays a significant role in the central nervous system, influencing synaptic plasticity, learning, and memory. This article will delve into the structure and function of the GRIN1 gene, its association with neurodevelopmental disorders, and the current state of drug development aimed at addressing these genetic conditions.

Structure and Function of the GRIN1 Gene

The GRIN1 gene encodes the GluN1 subunit, which is essential for the N-methyl-D-aspartate (NMDA) receptor. Belonging to the ionotropic family of glutamate receptors, NMDA receptors are ligand-gated ion channels permitting the movement of calcium (Ca²⁺), sodium (Na⁺), and potassium (K⁺) ions across neuronal membranes. Comprising 21 exons and undergoing alternative splicing, the GRIN1 gene found on chromosome 9q34.3 produces many isoforms that contribute to the functional variety of NMDA receptors.

Activating NMDA receptors calls for the neurotransmitter glutamate's attachment to the GluN1 subunit along with a co-agonist, either glycine or D-serine and membrane depolarization to remove the magnesium (Mg²⁺) barrier. NMDA receptors are guaranteed to be coincidence detectors vital for synaptic plasticity mechanisms by this dual-ligand need, which includes long-term potentiation (LTP) and long-term depression (LTD).

Figure 1 illustrates how a hypomorphic mutation in the Grin1 gene impacts NMDA receptor composition by reducing the NR1 subunit levels. This leads to fewer functional receptors, particularly affecting brain regions with naturally high NMDA receptor concentrations. Figure 1. A hypomorphic mutation in the Grin1 gene reduces the expression and protein levels of the NMDA receptor NR1 subunit.

GRIN1-Related Neurodevelopmental Disorders

A variety of neurodevelopmental diseases known as GRIN1-related neurodevelopmental disorders (GRIN1-NDD) are connected to mutations in the GRIN1 gene. Though their presentation differs, these conditions usually include developmental delay or intellectual impairment, seizures, hypotonia, mobility problems, and behavioral concerns. Some people also show polymicrogyria among other brain abnormalities.

GRIN1 de novo mutations have been linked to mobility abnormalities, cortical visual impairment, and major intellectual handicaps. Pathogenic GRIN1 mutations may lead to neurodevelopmental disorders with or without seizures, either autosomal dominant or recessive. For example, homozygous predicted-null mutations in GRIN1 have been linked to a much more severe outcome than those seen with homozygous missense variations.

Progress in Drug Development and Therapeutic Strategies

NMDA receptors have become targets for therapeutic intervention in many illnesses, including Alzheimer's disease, epilepsy, and neurodevelopmental disorders, because of their vital importance in brain functioning. Memantine and ketamine are two examples of antagonists that have been studied for their therapeutic value via altering NMDA receptor activation. Given their fundamental role in normal brain function, nevertheless, creating medications that properly change NMDA receptor activation without causing negative effects remains a major difficulty.

Recent research on certain GRIN1 mutations has improved our knowledge of their influence on NMDA receptor activity, hence clarifying the pathophysiology of GRIN1-related diseases. Studies on certain missense mutations have shown changes in receptor trafficking and function, hence guiding the creation of focused therapies.

Future Directions and Research

Continual studies seek to clarify the processes by which GRIN1 variation influences receptor activity and find possible treatment options. The creation of successful treatments depends on a knowledge of the precise molecular pathophysiology of GRIN1-related diseases. Hereditary engineering and pharmaceutical technology developments provide ongoing promise for new treatments that could reduce the effect of these hereditary diseases on those afflicted.

References:

Bhardwaj T, Ahmad I, Somvanshi P. Systematic analysis to identify novel disease indications and plausible potential chemical leads of glutamate ionotropic receptor NMDA type subunit 1, GRIN1. J Mol Recognit. 2023;36(1):e2997.
Liu Y, Wang Y, Chen S, et al. Glutamate ionotropic receptor NMDA type subunit 1: A novel potential protein target of dapagliflozin against renal interstitial fibrosis. Eur J Pharmacol. 2023;943:175556.
Čiháková D, Eaton WW, Talor MV, et al. Gut permeability and mimicry of the Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) as potential mechanisms related to a subgroup of people with schizophrenia with elevated antigliadin antibodies (AGA IgG). Schizophr Res. 2019;208:414-419.
Ramsey AJ. NR1 knockdown mice as a representative model of the glutamate hypothesis of schizophrenia. Prog Brain Res. 2009;179:51-58.

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