244 ISSN 1607-6729, Doklady Biochemistry and Biophysics, 2020, Vol. 494, pp. 244–247. © Pleiades Publishing, Ltd., 2020. Russian Text © The Author(s), 2020, published in Doklady Rossiiskoi Akademii Nauk. Nauki o Zhizni, 2020, Vol. 494, pp. 486–490. Dipeptide Mimetics of Different NGF and BDNF Loops Activate PLC-γ1 Corresponding Member of the RAS T. A. Gudasheva a, *, I. O. Logvinov a , S. V. Nikolaev a , T. A. Antipova a , P. Yu. Povarnina a , and Academician S. B. Seredenin a Received April 20, 2020; revised April 23, 2020; accepted April 23, 2020 Abstract—Previously, we designed and synthesized dipeptide mimetics of individual loops of the nerve growth factor (NGF) and the brain-derived neurotrophic factor (BDNF). It was shown that these mimetics activate the corresponding tyrosine kinase (Trk) receptors and have different patterns of activation of the PI3K/AKT and MAPK/ERK postreceptor signaling pathways in vitro. In the present study, it was shown on HT-22 cells that all these compounds activate the phospholipase C-γ1 (PLC-γ1) cascade. Keywords: BDNF, NGF, dipeptide mimetics, PI3K/AKT, MAPK/ERK, PLC-γ1 DOI: 10.1134/S1607672920050075 Neurotrophins are a group of closely related pro- teins from the family of growth factors that regulate the formation and essential functions of the central ner- vous system, including cell migration, neurite growth, synaptogenesis, cell survival and death, neuronal transmission, and synaptic plasticity [1–3]. By binding to tyrosine kinase (Trk) receptors, neu- rotrophins sequentially cause their homodimerization, autophosphorylation, and triggering of postreceptor sig- naling pathways—PI3K/AKT, MAPK/ERK, and PLC-γ1 [4, 5]. There is evidence that phosphorylation of Tyr490 (enumeration according to hTrkA) and sub- sequent recruitment of adapter proteins Shc and Frs 2 play the key role in the activation of MAPK/ERK and PI3K/AKT [4]. The activation of the PLC-γ1 pathway is initiated by direct binding of the phospholipase itself to phosphorylated Tyr783. Neurotrophins are homodimeric proteins, each monomer of which has four externally exposed loops [6, 7]. A hypothesis was put forward at the Zakusov Research Institute of Pharmacology that different loop structures of neurotrophins are responsible for their different biological functions, differentially acti- vating the postreceptor signaling pathways [8]. To test this hypothesis, mimetics of individual loops of neu- rotrophins, nerve growth factor (NGF), and brain- derived neurotrophic factor (BDNF) were obtained, namely: GK-6 and GK-2 for the first and fourth loops of NGF [8] and GSB-214, GTS-201, and GSB-106 for the first, second, and fourth loops of BDNF [9], respectively (Table 1) (RF patent no. 2410392, 2010; US patent no. US9683014 B2, 2017; patent of the European Patent Office EP 2397488, 2019; CN patent no. CN102365294 B, 2016). During construction, the most exposed dipeptide fragment of the loop β-turn was retained while the preceding amino acid residue was replaced with its bioisoster. To reproduce the dimeric structure of neurotrophin, dimerization at the C-terminus was performed with an oligomethylenedi- amide spacer. All the obtained dipeptide NGF and BDNF mimetics were shown to activate TrkA and TrkB receptors, respectively, on HT-22 immortalized mouse hippocampal cells with Western blot analysis [10, 11]. The dipeptides, in accordance with the pro- posed hypothesis, had different patterns of activation of the postreceptor signal transduction pathways PI3K/AKT and MAPK/ERK (Table 1) and different pharmacological activities. The mimetics of the fourth loop of NGF (GK-2) and the first loop of BDNF (GSB-214) activated only AKT, whereas the mimetic of the second loop of BDNF (GTS-201) activated ERK. Mimetics of the first loop of NGF (GK-6) and the fourth loop of BDNF (GSB-106) activated both pathways. All mimetics that activated AKT exhibited neuroprotective and antidiabetic activity. The mimet- ics that activated ERK modulated pain sensitivity, and the mimetics that activated both pathways exhibited antidepressant activity [12]. To further study the effect of loop structures of neurotrophins on the postreceptor signaling pathways, in this work we investigated the effect of dipeptide mimetics of individual loops of NGF and BDNF on the activation of the third postreceptor signaling path- way of Trk receptors, PLC-γ1. BIOCHEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY a Zakusov Research Institute of Pharmacology, Moscow, Russia *e-mail: tata-sosnovka@mail.ru