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Papers of the Week

Papers: 21 Dec 2019 - 27 Dec 2019

Pharmacology/Drug Development

2019 Dec 19

Sci Rep



Dual action of amitriptyline on NMDA receptors: enhancement of Ca-dependent desensitization and trapping channel block.


Stepanenko YD, Boikov SI, Sibarov DA, Abushik PA, Vanchakova NP, Belinskaia D, Shestakova NN, Antonov SM
Sci Rep. 2019 Dec 19; 9(1):19454.
PMID: 31857688.


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 Ca-dependent desensitization and 2) trapping channel block. Inhibition of NMDARs by ATL was found to be dependent upon external Ca concentration ([Ca]) in a voltage-independent manner, with an IC of 0.72 μM in 4 mM [Ca]. The ATL IC value increased exponentially with decreasing [Ca], with an e-fold change observed per 0.69 mM decrease in [Ca]. Loading neurons with BAPTA abolished Ca-dependent inhibition, suggesting that Ca affects NMDARs from the cytosol. Since there is one known Ca-dependent process in gating of NMDARs, we conclude that ATL most likely promotes Ca-dependent desensitization. We also found ATL to be a trapping open-channel blocker of NMDARs with an IC of 220 µM at 0 mV. An e-fold change in ATL IC was observed to occur with a voltage shift of 50 mV in 0.25 mM [Ca]. Thus, we disclose here a robust dependence of ATL potency on extracellular [Ca], and demonstrate that ATL bound in the NMDAR pore can be trapped by closure of the channel.