Abstract
Tricyclic antidepressants, specifically amitriptyline (ATL) and desipramine (DES) are currently used to treat depression and chronic pain of various origins, in which NMDA receptor dysfunctions play an important role. The effect of therapeutic ATL concentrations on calcium-dependent desensitization of NMDA receptors, driven by the level of free calcium in the cytoplasm, is well documented. In addition, in cardiomyocytes, ATL and DES can cause calcium release into the cytoplasm from intracellular stores by opening inositol-3-phosphate receptor (IP3R) and/or ryanodine receptors (RyR) channels. This aspect of ATL and DES effects on neurons remains poorly understood. We studied the dependence of calcium responses to DES and ATL on the activation of IP3R and RyR in the endoplasmic reticulum (ER) and mitochondria of rat neocortical neurons in primary culture. Short-term (30 s) paired (at a 5-min interval) applications of 200 µM DES or 200 µM ATL elicited similar-magnitude calcium responses in cortical neurons. The use of RyR and IP3R antagonists showed that responses to ATL are blocked by the IP3R antagonist 2-APB (100 µM), while responses to DES are blocked by the RyR antagonist ryanodine (100 nM). Since the intracellular distribution of RyR and IP3R is non-homogenous, it can be assumed that DES and ATL stimulate calcium release from different calcium stores located either in different segments of the ER or in the ER and mitochondria. In addition, ATL and DES, being channel blockers of NMDA receptors, inhibited calcium entry from the extracellular space via activated NMDA receptors. Considering high DES and ATL concentrations (>100 µM) required for the stimulation of calcium release in neurons, it seems unlikely that such effects appear during their therapeutic action. However, the revealed specificity of DES and ATL for RyR and IP3R, respectively, can be used as a tool for experimental purposes.
Similar content being viewed by others
REFERENCES
Rico-Villademoros F, Slim M, Calandre EP (2015) Amitriptyline for the treatment of fibromyalgia: a comprehensive review. Expert Rev Neurother 15(10):1123–1150. https://doi.org/10.1586/14737175.2015.1091726
Obata H (2017) Analgesic Mechanisms of antidepressants for neuropathic pain. Int J Mol Sci 18(11):2483. https://doi.org/10.3390/ijms18112483
Russell JW, Zilliox LA (2014) Diabetic neuropathies. Peripheral Nervous System Disorders 1226–1240. https://doi.org/10.1212/01.CON.0000455884.29545.d2
Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340 (2–3):249–258. https://doi.org/10.1016/s0014-2999(97)01393-9
Cusack B, Nelson A, Richelson E (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology 114 (4):559–565. https://doi.org/10.1007/BF02244985
Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R. (2012) Interactions of recombinant human histamine H1, H2, H3, and H4 receptors with 34 antidepressants and antipsychotics. Naunyn Schmiedebergs Arch Pharmacol 385(2):145–170. https://doi.org/10.1007/s00210-011-0704-0
Tohda M, Urushihara H, Nomura Y. (1995) Inhibitory effects of antidepressants on NMDA-induced currents in Xenopus oocytes injected with rat brain RNA. Neurochem Internat 26(1):53–58. https://doi.org/10.1016/0197-0186(94)00101-y
Barygin OI, Nagaeva EI, Tikhonov DB, Belinskaya DA, Vanchakova NP, Shestakova NN (2017) Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics. Brain Res 1660:58–66. https://doi.org/10.1016/j.brainres.2017.01.028
Stepanenko YD, Boikov SI, Sibarov DA, Abushik PA, Vanchakova NP, Belinskaia D, Shestakova NN, Antonov SM (2019) Dual action of amitriptyline on NMDA receptors: enhancement of Ca-dependent desensitization and trapping channel block. Sci Rep 9(1):19454. https://doi.org/10.1038/s41598-019-56072-z
Lavoie PA, Beauchamp G, Elie R (1990) Tricyclic antidepressants inhibit voltage-dependent calcium channels and Na+-Ca2+ exchange in rat brain cortex synaptosomes. Can J Physiol Pharmacol 68: 1414–1418. https://doi.org/10.1139/y90-215
Belinskaia DA, Belinskaia MA, Barygin OI, Vanchakova NP, Shestakova NN (2019) Psychotropic drugs for the management of chronic pain and itch. Pharmaceuticals 12(2):99. https://doi.org/10.3390/ph12020099
Boikov SI, Sibarov DA, Antonov SM (2020) Ethanol inhibition of NMDA receptors in calcium-dependent and -independent modes. Biochem Biophys Res Commun 522(4):1046-1051. https://doi.org/10.1016/j.bbrc.2019.12.007
Sibarov DA, Abushik PA, Poguzhelskaya EE, Bolshakov KV, Antonov SM (2015) Inhibition of plasma membrane Na/Ca-exchanger by KB-R7943 or lithium reveals its role in Ca-dependent N-methyl-D-aspartate receptor inactivation. J Pharmacol Exp Ther 355(3):484–495. https://doi.org/10.1124/jpet.115.227173
Sibarov DA, Poguzhelskaya EE, Antonov SM (2018) Downregulation of calcium-dependent NMDA receptor desensitization by sodium-calcium exchangers: a role of membrane cholesterol. BMC Neurosci 19(1):73. https://doi.org/10.1186/s12868-018-0475-3
Janowsky DS, Byerley B (1984) Desipramine: an overview. J Clin Psychiatry 45(10 Pt 2):3–9. PMID: 6384207
Sibarov DA, Antonov SM (2018) Calcium-dependent desensitization of NMDA receptors. Biochemistry (Mosc) 83(10):1173–1183. https://doi.org/10.1134/S0006297918100036
Zima AV, Qin J, Fill M, Blatter LA (2008) Tricyclic antidepressant amitriptyline alters sarcoplasmic reticulum calcium handling in ventricular myocytes. Am J Physiol Heart Circ Physiol 295(5):H2008–H2016. https://doi.org/10.1152/ajpheart.00523.2008
Joshi PG, Singh A, Ravichandra B (1999) High concentrations of tricyclic antidepressants increase intracellular Ca2+ in cultured neural cells. Neurochem Res 24:391–398. https://doi.org/10.1023/a:1020937717260
Chopra N, Laver D, Davies SS, Knollmann BC (2008) Amitriptyline activates cardiac ryanodine channels and causes spontaneous sarcoplasmic reticulum calcium release. Mol Pharmacol 75 (1):183-195. https://doi.org/10.1124/mol.108.051490
Furuichi T, Kohda K, Miyawaki A, Mikoshiba K (1994) Intracellular channels. Curr Opin Neurobiol 4:294–303. https://doi.org/10.1016/0959-4388(94)90089-2
Mironova EV, Evstratova AA, Antonov SM (2007) A fluorescence vital assay for the recognition and quantification of excitotoxic cell death by necrosis and apoptosis using confocal microscopy on neurons in culture. J Neurosci Methods 163:1–8. https://doi.org/10.1016/j.jneumeth.2007.02.010
Han EB, Stevens CF (2009) Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation. Proc Natl Acad Sci USA 106:10817–10822. https://doi.org/10.1073/pnas.0903603106
Ehrlich BE, Kaftan E, Bezprozvannaya S, Bezprozvanny I (1994) The pharmacology of intracellular Ca2+-release channels. Trends Pharmacol Sci 15:145–149. https://doi.org/10.1016/0165-6147(94)90074-4
Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K (1997) 2APB,2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J Biochem 122:498–505. https://doi.org/10.1093/oxfordjournals.jbchem.a021780
Saleem H, Tovey SC, Molinski TF, Taylor CW (2014) Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor. Br J Pharmacol 171(13):3298–3312. https://doi.org/10.1111/bph.12685
Palade P, Dettbam C, Brunder D, Stein P, Hals G (1989) Pharmacology of calcium release from sarcoplasmic reticulum. J Bioenerg Biomembr 21:295–319. https://doi.org/10.1007/BF00812074
Bezprozvanny I, Ondrias K, Kaftan E, Stoyanovsky DA, Ehrlich BE (1993) Activation of the calcium release channel (ryanodine receptor) by heparin and other polyanions. Molec Biol Cell 4:347–352. https://doi.org/10.1091/mbc.4.3.347
Missiaen L, Callewaert G, De Smedt H, Parys JB (2001) 2-Aminoethoxydiphenyl borate affects the inositol 1,4,5-trisphosphate receptor, the intracellular Ca2+ pump and the non-specific Ca2+ leak from the non-mitochondrial Ca2+ stores in permeabilized A7r5 cells. Cell Calcium 29 (2):111–116. https://doi.org/10.1054/ceca.2000.0163
Bilmen JG, Wootton LL, Godfrey RE, Smart OS, Michelangeli F (2002) Inhibition of SERCA Ca2+ pumps by 2-aminoethoxydiphenyl borate (2-APB). 2-APB reduces both Ca2+ binding and phosphoryl transfer from ATP, by interfering with the pathway leading to the Ca2+-binding sites. Eur J Biochem 269:3678–3687. https://doi.org/10.1046/j.1432-1033.2002.03060.x
Goto J, Suzuki AZ, Ozaki S, Matsumoto N, Nakamura T, Ebisui E, Fleig A, Penner R, Mikoshiba K (2010) Two novel 2-aminoethyl diphenylborinate (2-APB) analogues differentially activate and inhibit store-operated Ca2+ entry via STIM proteins. Cell Calcium 47:1–10. https://doi.org/10.1016/j.ceca.2009.10.004
Shimizu M, Nishida A, Yamawaki S (1993) Forskolin and phorbol myristate acetate inhibit intracellular Ca2+ mobilization induced by amitriptyline and bradykinin in rat frontocortical neurons. J Neurochem 61(5):1748–1754. https://doi.org/10.1111/j.1471-4159.1993.tb09812.x
Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131(3):596–610. https://doi.org/10.1016/j.cell.2007.08.036
Ryskamp DA, Korban S, Zhemkov V, Kraskovskaya N, Bezprozvanny I (2019) Neuronal Sigma-1 receptors: signaling functions and protective roles in neurodegenerative diseases. Front Neurosci 13:862. https://doi.org/10.3389/fnins.2019.00862
Verkhratsky A (2005) Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev 85:201–279. https://doi.org/10.1152/physrev.00004.2004
Walton PD, Airey JA, Sutko JL, Beck CF, Mignery GA, Südhof TC, Deerinck TJ, Ellisman MH (1991) Ryanodine and inositol trisphosphate receptors coexist in avian cerebellar Purkinje neurons. J Cell Biol 113(5):1145–1157. https://doi.org/10.1083/jcb.113.5.1145
Segal M, Vlachos A, Korkotian E (2010) The spine apparatus, synaptopodin, and dendritic spine plasticity. Neuroscientist 16:125–131. https://doi.org/10.1177/1073858409355829
Chen-Engerer HJ, Hartmann J, Karl RM, Yang J, Feske S, Konnerth A (2019) Two types of functionally distinct Ca2+ stores in hippocampal neurons. Nat Commun 10 (1):3223. https://doi.org/10.1038/s41467-019-11207-8
Fisar Z (2005) Interactions between tricyclic antidepressants and phospholipid bilayer membranes. Gen Physiol Biophys 24 (2):161-80. PMID: 16118470
Funding
This work was supported by the Russian Foundation for Basic Research (grant # 20-515-18008 Bolg_a) and budget funding within the State assignment to the Sechenov Institute of Evolutionary Physiology and Biochemistry (AAAA-A18-118012290427-7).
Author information
Authors and Affiliations
Contributions
Idea and experiment planning (D.A.S. and S.M.A.); experimental research (S.I.B. and T.V.K.); data processing (S.I.B. and D.A.S.); manuscript writing and editing (D.A.S. and S.M.A.)
Corresponding author
Ethics declarations
CONFLICT OF INTEREST
The authors declare that they have neither evident nor potential conflict of interest in relation to the publication of this article.
Additional information
Translated by A. Polyanovsky
Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, Nos. 4–5, pp. 629–640https://doi.org/10.31857/S086981392104004X.
Rights and permissions
About this article
Cite this article
Boikov, S.I., Sibarov, D.A., Karelina, T.V. et al. The Role of Ryanodine and IP3-receptors in Calcium Responses to Tricyclic Antidepressants in Rat Neocortical Neurons. J Evol Biochem Phys 57, 694–703 (2021). https://doi.org/10.1134/S0022093021030169
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0022093021030169