Increased CD38 may cause overexcitability of brain cells

Increased CD38 may cause overexcitability of brain cells

Not only is CD38 an NAD+ degrading enzyme, but it also plays a role in controlling intracellular calcium levels, which are critical for cell-to-cell communication in the brain and many other tissues. Too much calcium can lead to overexcitability of brain cells, which leads to brain damage.

CD38 plays a crucial role in controlling calcium levels by producing a tiny compound called cyclic ADP ribose (cADPR) from NAD+. Typically sitting on the outer membrane of cells with its enzymatic component facing the outside of the cell, activated CD38 consumes NAD+ and spits out, among other things, cADPR that can then be used by the cell to activate certain complexes, including calcium channels.

Several studies have shown that cADPR is involved in the activation of a molecular complex with channels that shuttle calcium critical for intercell communication in the hippocampus and other areas that have been linked to seizures. This complex consists of ryanodine receptors (Ryr), which release calcium stored up in a cellular structure called the endoplasmic reticulum into the fluid in the cell body (cytoplasm) of brain cells, and a protein called Fkbp-12.6 that is essential for regulating the activity of these ryanodine receptors. When Fkbp-12.6 is bound to the complex, the ryanodine receptors are shut down. But when it dissociates from the complex, the ryanodine receptors get activated.

What Khodaverdiana and colleagues found was that although there were no changes in ryanodine receptor levels in epileptogenesis, they saw a 20% reduction of Fkbp-12.6 protein levels. Khodaverdiana and colleagues think that increased levels of CD38 and decreased levels of Fkbp-12.6 might cause excessive stimulation of ryanodine receptors, which blasts brain cells with excitability and epilepsy that ultimately lead to their death.

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