The endogenous ionic channels represent an important class of transmembrane proteins directly involved in the regulation of an ion permeability of cell membranes. These proteins often are important elements of signaling and sensing pathways capable of connecting the inner space of the cell to extracellular side in a selective mode. For instance, the anion-selective channels and carriers can change pH regulation inside the cell by transporting anions across the plasma membrane. Resulting acidification of the cytoplasm may trigger the apoptosis of the cell, since alteration of the vital ionic and pH gradients between membranes has been considered its early event. This leads to believe that compounds capable of changing pH regulation in the cell can be applied for anticancer therapy treatment. Ionic channel- or carrier-facilitated passage of anions across the cell membranes can also be involved in maintaining the osmotic balance within the cell. Hence, there is a class of diseases, “chanelopathies” caused by faulty transport of mainly anions through cell membranes. These include muscular dystrophy, cystic fibrosis and myotonia, where impaired ionic flow primarily comprised of chloride across the plasma membrane results in changes of the volume of muscle fibers, the formation of sticky mucus in the organs containing epithelial cells, delayed relaxation of the skeletal muscles after voluntary or stimulated contraction, etc. (Haynes et al., 2014).

However, a free flow comprised mainly of physiologically significant cations (Ca2+, K+, Na+) vs chloride across the pores formed by different cation-selective ionophores or channels can also destroy the vital ionic gradients between membranes inflicting harm on the target cells via different modes of action bound with depolarization of cell membranes. The formation of almost indefinitely open and thus toxic pores by the well-known biocide, polyhexamethylene guanidine hydrochloride (PHMG) causes an efflux of K+ from bacterial cell that favors the mode of toxicity based on pore-formation in plasma membrane of susceptible cells as reported for the cationic antimicrobial macromolecules by (Brogden, 2005). This may result in the shrinkage and death of bacteria (Choi et al., 2016; Zhou et al., 2010) and primary human fibroblasts IMR-90 (Jung et al., 2014) or swelling of non-susceptible smooth muscle cells and synaptosomes (Paliienko et al., 2019). Depolarization of smooth muscle cells plasma membrane is also thought to result from the interaction between PHMG and Na+,K+-ATPase, which inhibited the enzymatic activity by 82.2 ± 0.9% (Paliienko et al., 2019). It is possible that PHMG-induced block of Na+,K+-ATPase may depolarize plasma membranes of the nerve terminals and blood platelets that reverses glutamate transporters increasing the ambient level of glutamate and intracellular concentration of Ca2+ via the channels of NMDA receptors in excitable membranes (Shigeri et al., 2004). High concentration of Ca2+ inside smooth muscle cells can be achieved due to increased concentration of intracellular Na+ after the PHMG-induced inhibition of Na+,K+-ATPase and subsequent activation of Na+/Ca2+−exchanger (Paliienko et al., 2019).

The dissipation of electrochemical gradients across the weakly cation-selective pores formed in excitable membranes by the nanoparticles of carbon nanodots synthesized from β-alanine and detonation nanodiamonds is likely to reverse the regular distribution of neurotransmitters by glutamate transporter that increases their ambient level thereby impairing synaptic transmission (Shatursky et al., 2022).

Also, despite the indications that the exocytosis in nerve tissues can be promoted by the alternative mechanisms (Storchak et al., 2002) there is growing evidence that ideally cation- and Ca2+-selective pores formed in the excitable membranes by latrotoxins of black widow spider venom provoke processes inside the nerve endings that finally lead to a massive neurotransmitter release into the synaptic gap (Filippov et al., 1994; Shatursky et al., 2007). Therefore, the type of envenomation known as latrodectism often results in muscle cramps, spasms and seizures of the pray.

A number of “channelopathies” with deficient transmembrane flow of ions and increasing evidence that anion transport can induce apoptosis in cancer cells are causing interest in the development of the synthetic molecular ion carriers and channels. There is the “faulty channel replacement therapy” approach, where a synthetic system such as a mobile carrier or channel is used to restore the lost permeability of cellular membranes. An attractive scaffold from which supramolecular systems may be constructed (Nimse and Kim, 2013; Giuliani et al., 2015) is offered by calixarenes due to the relatively easy introduction of different functional groups to the tetramer calix[4]arene base that makes its derivatives useful for a variety of applications including recognition and transport of ions as well as highly specific binding with ion pumps and membrane-bound enzymes (Veklich et al., 2014).

This paper represents the action of dibutoxycalix[4]arene thiocalix[4]arene-bis-α-hydroxymethylphosphonic acid (calix[4]arene C-1193) (Fig. 1) and several dipropoxycalix[4]arenes functionalized at the upper rim with the carboxyl groups (calix[4]arene C-424), hydroxyl groups and phosphonic acid residues (calix[4]arene C-425) (Fig. 1) upon conductivity of the sterol-containing phospholipid membrane, contractile ability and morphology of smooth muscle cells and synaptic transmission of the nerve tissue.

All calix[4]arenes were tested on the suspended cholesterol-egg PC planar bilayer phospholipid membranes in a voltage-clamp mode. Our contribution to the field of calix[4]arene-induced ionic transport and recognition is the finding that substitution of bridge carbons for sulphur at the lower rim of calix[4]arene-bis-α-hydroxymethylphosphonic acid (calix[4]arene C-99) (Fig. 1) transformed a former C-99-created anion carrier with the turnover rate of ∼20 cycles per sec [c-99 paper] into ionic channel formed by thiocalix[4]-arene-bis-α-hydroxymethylphosphonic acid (calix[4]arene C-1193) in bilayer membrane. Thus, the addition of calix[4]arene C-1193 to the extracellular space could increase the transmembrane flux of ions at least 10 (Zhou et al., 2010)-fold as compared with calix[4]arene C-99.

The membrane action of calix[4]arene C-1193 assessed on isolated presynaptic rat cortex nerve terminals (synaptosomes) caused the depolarization of excitable membrane and increased ambient level of neurotransmitters, while the calix[4]arene C-1193 treated smooth muscle cells of a rat uterus exhibited increased concentration of intracellular Ca2+ and reduced hydrodynamic diameter of the cells. Obtained results suggest that calix[4]arene C-1193-induced membrane depolarization results in diverse modes of action that eventually lead to the impaired synaptic neurotransmission and contraction of the smooth muscle.