Studium funkčních a farmakologických vlastností glutamátových receptorů

Kysilov, Bohdan

N-methyl-D-Aspartate receptors (NMDAR) are ionotropic glutamate receptors that are involved in the regulation of nearly every process in the brain. Therefore, even a subtle disturbance in NMDAR function may result in severe pathological consequences. Loss-of- function mutations in the NMDAR-encoding genes have been implicated in numerous neuropsychiatric disorders, including intellectual disability, developmental delay, schizophrenia, autism spectrum disorders, epilepsy, and movement disorders. Insufficient NMDAR function can be rectified by positive allosteric modulators, including neurosteroids; however, the mechanism underlying the potentiating effect of steroids is not well understood. By employing patch-clamp electrophysiology we assessed the effect of newly synthesized neurosteroid-like pregnane analogues on recombinant GluN1/GluN2B receptors. We demonstrated that compounds with short C3 residues, such as pregnanolone acetate (PA- Ace) and pregnanolone carboxylate (PA-Car), are negative modulators of NMDAR, whereas compounds with longer C3 residues, such as pregnanolone butyrate (PA-But) and epipregnanolone butyrate (EPA-But), are positive modulators of NMDARs. Furthermore, we revealed that EPA-But has a disuse-dependent positive allosteric effect, being similar in that regard to endogenous...

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