Interactions of drugs and toxins with permeant ions in potassium, sodium, and calcium channels

Ion channels in cell membranes are targets for a multitude of ligands including naturally occurring toxins, illicit drugs, and medications used to manage pain and treat cardiovascular, neurological, autoimmune, and other health disorders. In the past decade, the x-ray crystallography revealed 3D structures of several ion channels in their open, closed, and inactivated states, shedding light on mechanisms of channel gating, ion permeation and selectivity. However, atomistic mechanisms of the channel modulation by ligands are poorly understood. Increasing evidence suggest that cationophilic groups in ion channels and in some ligands may simultaneously coordinate permeant cations, which form indispensible (but underappreciated) components of respective receptors. This review describes ternary ligand-metal-channel complexes predicted by means of computer-based molecular modeling. The models rationalize a large body of experimental data including paradoxes in structure-activity relationships, effects of mutations on the ligand action, sensitivity of the ligand action to the nature of current-carrying cations, and action of ligands that bind in the ion-permeation pathway but increase rather than decrease the current. Recent mutational and ligand-binding experiments designed to test the models have confirmed the ternary-complex concept providing new knowledge on physiological roles of metal ions and atomistic mechanisms of action of ion channel ligands.     

Effect of thallium ions on sodium and potassium transport in frog skin

It has been shown that Tl+ accumulated in the frog skin cells (Rana temporaria) inhibits irreversibly the unidirectional transport of Na+ estimated by the short circuit current (SCC). The inhibiting effect of Tl+ cannot be attributed to a decrease of Na+ penetration through the apical membranes. The influx of 22Na+ from mucosal bathing solution into the skin poisoned with Tl+ was about 50% of that observed in the intact skin, while the SCC was completely inhibited. The activity of the ouabain-sensitive Na+/K+ pumps located in the basolateral cell membranes was estimated by studying the uptake of 86Rb+ as a tracer for K+. This activity was high enough to maintain the ion composition of epithelial cells in spite of their ability to accomplish the undirectional transport of Na+. Tl+ seems to inhibit the production of respiration energy utilized in the undirectional Na+ transport, while the ion homeostasis of epithelial cells may be supported by the Na+/K+ pumps consuming energy of glycolytic reactions.     

Effect of calcium ions on potassium conductivity of latrotoxin channels

It has been shown that inhibition of potassium current through latrotoxin channels by calcium ions is followed by electrostatic interaction of these ions with a total charge on the mouth of the channel.     

Effects of sodium, potassium and calcium on salt-stressed barley

We grew barley ( Hordeum vulgare L. CM 72) for a 28-day period and sequentially harvested plants every 3 or 4 days. Plants were salt-stressed with either NaCl or KCl (125 m M ) with or without supplemental Ca (10 or 0.4 m M final concentration, respectively). We determined tissue concentrations of Na, Ca, Mg, K. S, P, Fe, Mn, Cu and Zn for each harvest date by inductively coupled plasma spectrometry. Uptake (specific absorption rate) was calculated from the element content and growth rates. Salinity had significant effects on the uptake and concentrations of most elements. Mg and Mn concentrations declined with time. The concentrations of all other elements determined increased over time. Element uptake on a root dry weight basis declined with time. Three variables were significantly affected by salinity and correlated with growth; 1) the Ca concentration, 2) the total sum of the cation concentration (TC), and 3) the Mn concentration of the shoot. Salinity reduced Ca uptake and concentrations. Supplemental Ca increased Ca concentrations and was positively correlated with growth during salt stress. Salinity doubled TC, which was negatively correlated with relative growth rate (RGR). Relative growth rate declined at TC values above 150 m M . Salinity reduced the uptake and concentration of Mn. Manganese concentrations in the shoot were highly correlated with RGR. Relative growth rate declined at Mn concentrations below 50 nmol (g fresh weight)⁻¹.     

Effects of extracellular potassium ions on outward potassium current dependent on extracellular calcium ions

Changes in outward potassium current occurring in response to changes in the concentration of potassium ions in the extracellular medium were investigated in unidentified neurons isolated fromHelix pomatia using an intracellular perfusion technique. It was found that introducing potassium ions (5–10 mM) into the extracellular solution produces a reversible increase in the component of outward potassium current which is dependent on extracellular calcium ions. Increased amplitude of this component occurs as a result of attenuated inactivation of the current under the action of extracellular potassium.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 19, No. 3, pp. 351–356, May–June, 1987.     

Effect of sodium and potassium ions on conformation of linker parts of nucleosomes

The chromatin structure and DNA accessibility to proteins depend on the structure of linker DNA entering and exiting the nucleosome. Since DNA is a negatively charged polymer, the conformation of linker DNA, in turn, depends on the ionic microenvironment. In the present work, the effect of Na⁺ and K⁺ ions on the structure of mono nucleosome linker DNA was studiedby fluorescence microscopy of single complexes. It was revealed that nucleosomes adopt one of two conformational states, whose occupancy is significantly changed after the substitution of K⁺ ions by Na⁺. These changes are likely caused by different interaction of Na⁺ and K⁺ with DNA in the regions of DNA entry and exit of the nucleosome. Cation-dependent changes in the conformation of linker DNA may affect topological barriers in the nucleosome, structure of polynucleosome chromatin, and interactions with different protein factors.     

Effect of ammonium,sodium, and potassium ions on rabbit muscle phosphofructokinase-1 and adenylate kinase activities

This report shows that 30 nM PFK-1 and 30 nM AK were both affected by the presence of NH₄⁺, Na⁺, and K⁺ salts but with opposite consequences. Low concentrations of PFK-1 lose about half of its activity as a result of dilution and become susceptible to further activity losses owing to the presence of monovalent salts. On the other hand low concentrations of AK lose about 75 percent of its activity but regains activity losses owing to the presence of monovalent salts. It was determined that regain of AK activity did not appear to be a reflection of a major effect on the K_m value of either AMP or ATP. Dilution to 30 nM AK resulted in no increase K_m values compared to K_m values at 140 nM AK. Dilution caused major decreases in the maximum velocities, V_max, when ATP or fructose 6-phosphate was the variable substrate. It was shown in earlier reports that these same low concentrations of PFK-1 and AK were susceptible inhibitions by ascorbate. These attributes are discussed as they may relate to the role of ascorbate facilitation glycogen synthesis in resting muscle and the role that the cytoskeleton infrastructure scaffold may play is also discussed.     

The receptor potential of retinular cells of the blowflyCalliphora: The role of sodium,potassium and calcium ions

Summary Simultaneous membrane potential and membrane resistance measurements and current clamp experiments were performed on the visual sense cells ofCalliphora. The results suggest that the receptor potential is due to two different conductance variations: (i) a conductance increase for both Na⁺- and K⁺-ions upon illumination, and (ii) a light-independent conductance increase for K⁺-ions. Evidence is obtained that in the visual sense cells ofCalliphora the light-independent conductance increase is mediated by the influx of Ca²⁺-ions.The conclusion is that the increase of the intracellular Ca²⁺-ion concentration not only decreases the light-induced conductance, but also increases the light-independent conductance. So the potential of the sense cell is governed by two antagonistic conductances. The functional advantages of such a system are discussed.     

Effect of interleukin-1 on intracellular concentration of sodium, calcium, and potassium in 70Z/3 cells

The cytokine interleukin-1 (IL-1) has been shown to induce the differentiation of a murine pre-B like cell line 70Z/3. An early intracellular event caused by exposure to IL-1 is an amiloride-sensitive progressive rise in the total concentration of intracellular sodium ([Na]i), caused by influx of Na+ from outside, and a transient fall in total intracellular calcium. The results suggest that IL-1-induced influx of Na+ into 70Z/3 occurs via stimulation of the Na+/H+ antiport. IL-1-induced differentiation is also blocked by amiloride suggesting that stimulation of Na+/H+ exchange may play a role in IL-1-induced differentiation.     

Free concentrations of sodium, potassium and calcium in chromaffin granules.

We have measured the contents of Na+ and K+ in isolated chromaffin granules. Total contents varied between 227 and 283 nmol/mg of protein, equivalent to matrix concentrations of 53-66 mM. The value found depended on the isolation buffer used, and the ratio of the two ions reflected the composition of the buffer. We then measured the free concentration of each of these ions, and of Ca2+, in the matrix, by using a null-point method with acridine-fluorescence quenching. This monitored H+ fluxes induced by an ionophore in the presence of known concentrations of the ion in the supporting medium. In contrast with organic constituents of the matrix, which have low activity coefficients, Na+ and K+ were found to have activity coefficients around 0.8 Ca2+, however, was strongly bound: its free concentration was only 0.03% of the total.     

Intracellular activities of chloride, potassium and sodium ions in rabbit corneal epithelium

The mechanism of ion transport in the epithelium of rabbit cornea was studied by determining the intracellular ion activity of Cl-, Na+ and K+ under various conditions. Ionic activities were measured by means of microelectrodes containing liquid ion-exchangers selective for Cl-, Na+ or K+. The Cl- activity in basal cells of the epithelium in Na+ containing bathing solutions amounts to 28 +/- 2 mM (n = 11). This value is 1.9-times greater than expected on the basis of passive distribution across the tear side membrane. This finding suggests the existence of a Cl- accumulating process. Replacement of Na+ in the aqueous bathing solution by choline or tetraethylammonium results in a reversible decrease in Cl- activity to 22 +/- 1 mM (n = 11, P less than 0.025). The ratio of observed and predicted Cl- activity decreased significantly from 1.9 to 1.4 (P less than 0.05). The decrease in Cl- activity due to Na+ replacement was rather slow. In contrast, after readmittance of Na+ to the aqueous bathing solution, Cl- activity rose to a stable level within 30 min. These results indicate involvement of Na+ in Cl- accumulation into the basal cells of the epithelium. The K+ and Na+ activities of the basal cells of rabbit corneal epithelium in control bathing solutions were 75 +/- 4 mM (n = 13) and 24 +/- 3 mM (n = 12), respectively. The results can be summarized in the following model for Cl- transport across corneal epithelium. Cl- is accumulated in the basal cells across the aqueous side membrane, energized by a favourable Na+ gradient. Cl- will subsequently leak out across the tear side membranes. Na+ is extruded again across the aqueous side membrane of the epithelium by the (Na+ + K+)-ATPase.