Dual action of amitriptyline on NMDA receptors: enhancement of Ca-dependent desensitization and trapping channel block
| Autor: | Natalia N. Shestakova, Sergei I. Boikov, P. A. Abushik, Daria A. Belinskaia, Yulia D. Stepanenko, D. A. Sibarov, Nina Pavlovna Vanchakova, Sergei M. Antonov |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Patch-Clamp Techniques lcsh:Medicine Gating Antidepressive Agents Tricyclic Ion channels in the nervous system Membrane Potentials chemistry.chemical_compound 0302 clinical medicine Cytosol immune system diseases hemic and lymphatic diseases Amitriptyline Receptor lcsh:Science Cells Cultured Cerebral Cortex Neurons Multidisciplinary Chemistry Depression NMDA receptor Female Chronic Pain Ion Channel Gating medicine.drug Primary Cell Culture Receptors N-Methyl-D-Aspartate Article 03 medical and health sciences Inhibitory Concentration 50 BAPTA Cellular neuroscience medicine Animals Humans Patch clamp Ion transporter Ion transport lcsh:R Rats 030104 developmental biology nervous system Biophysics Neuralgia lcsh:Q Calcium Extracellular Space 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-15 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Although the tricyclic antidepressant amitriptyline (ATL) is widely used in the clinic, the mechanism underlying its high therapeutic efficacy against neuropathic pain remains unclear. NMDA receptors (NMDARs) represent a target for ATL and are involved in sensitization of neuropathic pain. Here we describe two actions of ATL on NMDARs: 1) enhancement of Ca2+-dependent desensitization and 2) trapping channel block. Inhibition of NMDARs by ATL was found to be dependent upon external Ca2+ concentration ([Ca2+]) in a voltage-independent manner, with an IC50 of 0.72 μM in 4 mM [Ca2+]. The ATL IC50 value increased exponentially with decreasing [Ca2+], with an e-fold change observed per 0.69 mM decrease in [Ca2+]. Loading neurons with BAPTA abolished Ca2+-dependent inhibition, suggesting that Ca2+ affects NMDARs from the cytosol. Since there is one known Ca2+-dependent process in gating of NMDARs, we conclude that ATL most likely promotes Ca2+-dependent desensitization. We also found ATL to be a trapping open-channel blocker of NMDARs with an IC50 of 220 µM at 0 mV. An e-fold change in ATL IC50 was observed to occur with a voltage shift of 50 mV in 0.25 mM [Ca2+]. Thus, we disclose here a robust dependence of ATL potency on extracellular [Ca2+], and demonstrate that ATL bound in the NMDAR pore can be trapped by closure of the channel. |
| Databáze: | OpenAIRE |
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