Cytolytic peptides are a large, heterogeneous group of proteinaceous compounds capable of disrupting the integrity of biological membranes and causing cell lysis. Arthropod venom is a rich source of cytolytic peptides. Melittin from honeybee venom, as well as several peptides from the venom of the spider Lachesana tarabaevi, have previously been demonstrated to inhibit the growth of the intracellular parasitic bacterium Chlamydia trachomatis. In this study, using the Tet-On system for regulated gene expression in HEK293 cells, it was demonstrated that oxyopinins—cytolytic peptides derived from the venom of the spider Oxyopes takobius—exhibit similar anti-chlamydial activity. Oxyopinins have diverse amino acid sequences and are not homologous to previously studied peptides. This work significantly expands the range of known compounds with anti-chlamydial activity.
In this work we investigated the pore-forming activity of ShlA toxin from Serratia proteamaculans in lipid bilayers modelling the membranes of epithelial cells HeLa and Caco-2 and assessed the role of CaCl2 in its modification. It was found that the addition of conditioned S. proteamaculans media enriched with ShlA toxin to planar lipid bilayers formed from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/sphingomyelin (SM)/cholesterol (CHOL) (33/33/33 mol
Two-pore calcium channels (TPCs) are localized in the membranes of endosomes and lysosomes and play a crucial role in the regulation of vesicular transport, autophagy, protein, nucleic acid, and lipid catabolism, recycling of plasma membrane receptors, and other processes occurring in the endolysosomal system. Humans express two types of channels, TPC1 and TPC2. Dysfunction of these channels is the cause of severe pathologies, including cancer and neurodegenerative diseases. Understanding the mechanisms of TPC channel regulation and identifying pharmacological pathways to influence their activity are essential for developing new approaches to the prevention and treatment of these diseases. This review characterizes the properties of two-pore channels and describes their regulation by phosphatidylinositol-3,5-bisphosphate and NAADP (nicotinic acid adenine dinucleotide phosphate), changes in channel activity during cell starvation, as well as the effects on TPC channels exerted by sphingosine, protein kinases P38 and JNK, and regulatory proteins mTor, Rab7a, and Tmem63a. Information on the pharmacology of TPC channels is provided. Groups of NAADP receptor site antagonists and compounds acting directly on the channel protein are highlighted. Part of the review is devoted to the description of plant-derived channel regulators and their potential use as anticancer drugs.
One of the problems of modern neuropharmacology is the search for new structures that affect specific targets in the nervous system. Among such promising structures is diazepinobenzimidazole, which includes two privileged subclasses: diazepine and benzimidazole. One of its derivatives, DAB-19, demonstrates a wide range of activities and appears to be very promising. However, the targets of DAB-19 and the molecular mechanisms of its action remain poorly understood. DAB-19 inhibits AMPA- and NMDA-subtypes of glutamate receptors, blocks voltage-gated sodium channels, and enhances spontaneous synaptic release of glutamate. This complex action profile complicates the analysis of action mechanisms. In this study, we investigated the effects of several analogues of DAB-19 to separate the action on different targets by structure–function analysis. We found that the presence of a side chain in diazepinobenzimidazole derivatives is necessary for both stimulating spontaneous release and blocking sodium channels. The presence of a long side chain containing an aromatic ring is critical for stimulating spontaneous release. Compounds with a shorter radical with a saturated ring lose their ability to stimulate spontaneous release but retain their ability to block sodium channels. The results are important for the further targeted design of new compounds that modulate the functions of the central nervous system (CNS).
The first messengers regulate cellular functions by involving surface receptors coupled to diverse intracellular signaling pathways. Those do not function completely independently, and an increasing body of evidence argues for the existence of crosstalk between signaling systems and their coordination. Here we analyzed a potential contribution of the PI3K–Akt cascade to the regulation of cAMP signaling initiated by noradrenaline (NA) in HEK-293 cells that expressed Pink Flamindo, a genetically encoded cAMP sensor, at a constant and high level. This feature makes this cell line a sufficiently effective cellular model for the analysis of mechanisms involved in the generation of intracellular cAMP signals. As was shown, the stimulation of β‑adrenoreceptors (β-AR) by NA led to a rise in cAMP in HEK-293 cells. Being applied shortly for 100–150 s, NA initiated cAMP signals, the magnitude of which gradually increased with an agonist concentration, exhibiting the EC50 of about 1 µM. In the presence of 150 nM insulin, the magnitude of cAMP responses to 1 µM NA decreased by 31
