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Amphotericin B Membrane Action: Role for Two Types of Ion Channels in Eliciting Cell Survival and Lethal Effects

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Abstract

The formation of aqueous pores by the polyene antibiotic amphotericin B (AmB) is at the basis of its fungicidal and leishmanicidal action. However, other types of nonlethal and dose-dependent biphasic effects that have been associated with the AmB action in different cells, including a variety of survival responses, are difficult to reconcile with the formation of a unique type of ion channel by the antibiotic. In this respect, there is increasing evidence indicating that AmB forms nonaqueous (cation-selective) channels at concentrations below the threshold at which aqueous pores are formed. The main foci of this review will be (1) to provide a summary of the evidence supporting the formation of cation-selective ion channels and aqueous pores by AmB in lipid membrane models and in the membranes of eukaryotic cells; (2) to discuss the influence of membrane parameters such as thickness fluctuations, the type of sterol present and the existence of sterol-rich specialized lipid raft microdomains in the formation process of such channels; and (3) to develop a cell model that serves as a framework for understanding how the intracellular K+ and Na+ concentration changes induced by the cation-selective AmB channels enhance multiple survival response pathways before they are overcome by the more sustained ion fluxes, Ca2+-dependent apoptotic events and cell lysis effects that are associated with the formation of AmB aqueous pores.

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Notes

  1. The KK equations (Kedem and Katchalsky 1958) assumed that the mechanism of osmotic water flow is the same as for pressure-driven flow, resulting in equal reflexion coefficients for osmosis and ultrafiltration. This asumption was proven to be incorrect and replaced by a bimodal theory of osmosis in which osmosis and ultrafiltration have distinct reflection coefficients (defined as σs and σf for osmosis and ultrafiltration, respectively) (Hill 1982). The basic idea in the bimodal theory of osmosis is that water transfer across membrane pores occurs by diffusion if the driving osmolytes have access to the pore. Otherwise, when the solute cannot enter the pore (in the so-called impermeable or semipermeable pores), a pressure gradient is established, resulting in viscous flow across the entire length of the channel. Calculations of the maximal values for the osmotic permeabilities across water channels of different pore radius (r p) such as aquaporin (r p = 2.0–2.5 Å), gramicidin (r p = 2.5 Å) and nystatin or AmB (r p = 4 Å) were found to be about one order of magnitude greater than for diffusive flows, in close agreement with the experimental data (Hill 1994). The reflection coefficients determined for the aqueous pores formed by nystatin and AmB in planar bilayers (Finkelstein and Holz 1973) are also in very good agreement with the values calculated using the expression for σs (Hill 1982).

  2. In pure lipid membranes, a solute such as urea permeates by dissolution in the membrane, so it is to be expected that σs for urea = 1.0 when [AmB] = 0. We calculated σ = 0.8 using the ratio of the initial slopes (dV/dt (t=0)) with urea and glucose at the same osmolarity (see Fig. 1 in Cohen 1998). The reason for the control value being smaller than 1 is not clear, but it can be partly due to glucose not being completely impermeable. However, if the value obtained for the AmB aqueous pores is corrected by this difference, it yields essentially the value of σs = 0.57 that was obtained for the aqueous pores formed by adding nystatin or AmB to one side (Kleinberg and Finkelstein 1984) or to both sides of planar lipid bilayers (Finkelstein and Holz 1973).

  3. An inverse relationship between the equilibrium constant K and the affinity (concentration) for the formation of AmB channels can be derived by applying the Scatchard equation as modified by Friguet et al. (1985) to calculate affinities when in an experiment the concentration of free antibodies is evaluated instead of concentrations of antigen–antibody complexes.

  4. While in the vertical position, the amino and carboxyl groups at one end of the polyene antibiotic (Fig. 1) are known to interact strongly with the polar heads of the phospholipids rather than with the hydrophobic core (Sternal et al. 2004; Gabrielska et al. 2006). This orientation is not expected to be the preferred mode of membrane insertion of AmB monomers from the water phase due to the predominance of electrostatic forces.

  5. Hill coefficients ranging from 3.0 to 5.0 were calculated from the earliest (just after mixing) polyene-induced osmotic changes that were measured at concentrations leading to the formation of ion channels across ergosterol-containing membranes (Cohen et al. 1986). Such Hill coefficients can be taken as the number of units (possibly dimers, see Gruszecki et al. 2003) that interacting in a cooperative event are needed to form the postulated eight-monomer ring structure that creates a channel with a 4 Å radius (De Kruijff and Demel 1974; see also Baginski et al. 1997).

  6. In liposomes prepared free of sterols, AmB is able to induce the formation of cation-selective nonaqueous pores at concentrations similar to that required in cholesterol-containing liposomes (e.g., ≥0.5 × 10−6 M) but concentrations as high as 10 × 10−6 M AmB are needed to detect the first indications of the formation of aqueous pores (Table 1).

  7. The interfacial energy—also known as “line tension”—is the result of a hydrophobic thickness mismatch between the lipid rafts and those in the surrounding membrane. The formation of AmBaq-pores at the boundaries of the lipid rafts may contribute to reduce the line tension by the formation of AmB–sterol complexes that produce a thickness decrease by locally removing cholesterol molecules from interactions with phospholipid molecules. Interestingly, AmB has been shown to enhance the transbilayer mobility of phospholipids in erythrocyte membranes, an effect that disrupts the asymmetric distribution of aminophospholipids (Schneider et al. 1986). As discussed previously (Romero et al. 2009), the loss of phospholipid membrane asymmetry in erythrocyte membranes (Lange et al. 2007) may produce an increased exposure of the cholesterol at the outer leaflet that may facilitate the direct interaction of AmB with the sterol (Szponarski and Bolard 1987).

  8. The dose-dependent inhibition by AmE of the entry mechanism of HIV-1 into cells was significantly increased from 1 to 4.0 × 10−6 M AmE, a concentration range at which AmBaq-pores are predominantly formed in the cholesterol/SPM-rich lipid rafts of human erythrocyte membranes (Romero et al. 2009). Both AmE and AmB are known to induce their permeabilizing activity in human erythrocytes at essentially the same concentrations (Bolard 1986).

  9. The Mapk1 pathway, which is also referred to as the cell integrity/PKC pathway, is one of the yeast signal-transduction pathways that is essential for sensing the integrity of the cell wall under environmental stresses such as hypo-osmotic shock (Davenport et al. 1995), high temperatures (Kamada et al. 1995) or exposure to inhibitors of the synthesis of essential cell wall components (Levin 2005). Activation of the cell integrity/PKC pathway proceeds from the stimulation of plasma membrane proteins (Mid2, Wsc1-4) that interact with the guanine nucleotide exchange factors (Rom1 and Rom2) for Rho1 GTPase (a small Ras-like protein), which in turn activates PKC and the MAP kinase cascade (Qi and Elion 2005). Deletion of genes such as Rom2 or those of other proteins that participate in the cell integrity/PKC pathway exhibits a temperature-sensitive cell lysis phenotype that is suppressed by the external addition of impermeant solutes as osmotic stabilizers (Cid et al. 1995). In Candida and other fungi, a Ras/cAMP-signaling pathway also controls osmotic and other stress responses that are critical for keeping the wall integrity via activation of PKA (Harcus et al. 2004). A connection between the cell integrity/PKC and RAS/cAMP pathways has been recently demonstrated in yeast via the shared protein Rom2 (Park et al. 2005).

  10. A genomewide fitness and expression profile using yeast cells to understand the molecular pathways involved in the so-called adaptive response to oxidative stress found that mild pretreatment of cells with H2O2 produced a significant decrease of ergosterol content but the level of Fas1 mRNA levels increased (Kelley and Ideker 2009). This study was able to identify Mga2, a transcription factor, as an important gene in the yeast adaptation to H2O2 exposure. This transcription factor has been implicated in fatty acid biosynthesis and in the response to hypoxia (Kelley and Ideker 2009).

  11. The dissipation of the proton gradient by AmB across the membrane is greatly enhanced by the formation of AmBaq-pores as shown by the relatively higher concentrations of AmB and nystatin that were needed to collapse the proton gradient in yeast cells (Palacios and Serrano 1978). In effect, it is known that the AmBnonaq channels have a very low permeability to protons (Cybulska et al. 1995) that increased via the AmBaq-pores (Cohen 1998). These permeability properties of the AmB channels formed are consistent with the results obtained with Candida cells treated with low AmB concentrations that have indicated that under these conditions the replication competence, intracellular ATP levels and negative membrane potential are maintained (Liao et al. 1999).

  12. At concentrations below 0.1 × 10−6 M AmB, Brajtburg et al. (1984) also found that AmB induced an enhancement of plating efficiency of L cells and other stimulatory effects on the incorporation of uridine and thymidine into RNA and DNA, respectively.

  13. Increasing evidence supports that K+ depletion from cells has a direct effect on the activation of the proinflammatory cytokines IL-1β and IL-18 into their mature active forms in NLRP3 and NLRP1 inflammasomes (Aroian and van der Goot 2007; Petrilli et al. 2007).

  14. The results by Zager (2000) in mammalian cells are opposite to those obtained in Candida cells by Liu et al. (2005) that indicated the downregulation by AmB of a set of genes coding for proteins responsible of the synthesis of ergosterol, long-chain saturated fatty acids and ceramide. It appears that such opposite trends in the observed responses can be related to the quite distinct concentrations used in the fungal versus mammalian cell experiments, which is the main factor for determining that either AmBnonaq or AmBaq-pores are formed, affecting different pathways.

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    B. Eleazar Cohen

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Cohen, B.E. Amphotericin B Membrane Action: Role for Two Types of Ion Channels in Eliciting Cell Survival and Lethal Effects. J Membrane Biol 238, 1–20 (2010). https://doi.org/10.1007/s00232-010-9313-y

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