Introduction to GRID disorder

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GRID1 and GRID2 encode the delta receptors GluD1 and GluD2. Although these receptors are often found in the same place as NMDARs, AMPARs and KARs, the way they work is less clear, and probably quite different.

Despite their resemblance to AMPARs and KARs and the potential for four subunits to form an ion channel, it remains unclear whether this ion channel is utilized by neurons. Evolutionary changes might have rendered the ion channel unnecessary, and even though delta receptors share a general shape with other iGluRs, it’s uncertain whether it can open when neurotransmitters bind. This area is a subject of ongoing scientific research.

Even though we aren’t sure if they can act as an ion channel carrying electrical currents, the delta receptors are certainly very important. They help form and anchor the connections between neighboring brain cells, and if either of the GRID genes is defective, this can lead to problems in the affected areas of the brain, impacting both early development and later life.

Unlike NMDARs the delta subunits only form receptors containing four of the same subunits i.e. only GluD1 subunits, or only GluD2 subunits. The differences between their function in the brain, and the symptoms of GRID1 vs GRID2 patients, are largely influenced by the brain regions where each receptor is predominantly found.  For example, GRID2 disorder is associated with Spinocerebellar Ataxia 18, a movement disorder, due to its high presence in the cerebellum, a critical region for movement control.

From what we know about GRID disorder so far, it appears to result mainly from one of two mechanisms, which are subtly different from those of most of the other GRI disorders. The first requires a patient to have two defective copies of a GRID gene affecting the ability of brain cells to form electrical connections with each other. The second is that variants can occur which lead to the ion channel (which as stated above, may or may not be designed to open) being partially opened the whole time. This leads to abnormal and damaging electrical signals in brain cells.

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