Phospholipid Flip-Flop and the Distribution of Surface Charges in Excitable Membranes

McLaughlin, Stuart; Harary, Howard

doi:10.1016/s0006-3495(74)85907-2

Cited by 71 publications

(29 citation statements)

References 11 publications

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“…This conforms at least qualitatively to the theoretical expectation that generally the density of negatively charged entities should be smaller on the inner face of the membrane than on the outer face (McLaughlin & Harary, 1974). Then Eqs.…”

Section: Application Of the Theoretical Model Of Ca 2 +-Dependent Regsupporting

confidence: 88%

Regulation of passive potassium transport of normal and transformed 3T3 mouse cell cultures by external calcium concentration and temperature

Ernst

Adam

1981

J. Membrain Biol.

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Regulation of passive potassium ion transport by the external calcium concentration and temperature was studied on cell cultures of 3T3 mouse cells and their DNA-virus transformed derivatives. Upon lowering of external calcium concentration, passive potassium efflux generally exhibits a sharp increase at about 0.1 mM. The fraction of calcium-regulated potassium efflux is largely independent of temperature in the cases of the transformed cells, but shows a sharp increase for 3T3 cells upon increasing temperature above 32 degrees C. In the same range of temperature, the 3T3 cells exhibit the phenomenon of high-temperature inactivation of the residual potassium efflux at 1 mM external calcium. At comparable cellular growth densities, the transformed cell lines do not show high-temperature inactivation of "residual" potassium efflux. These results are consistent with the notion of a decisive role of the internal K+ concentration in the cell-density dependent regulation of cell proliferation. In particular, the growth-inhibiting effect of lowering the external Ca2+ concentrations is considered as largely due to a rise of passive K+ efflux and a subsequent decrease of internal K+ concentration. The experimental data on the Ca2+ dependence of passive K+ flux are quantitatively described by a theoretical model based on the constant field relations including negative surface charges on the external face of the membrane, which cooperatively bind Ca2+ ions and may concomitantly undergo a lateral redistribution. The present evidence is consistent with acidic phospholipids as representing these negative surface charges.

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Section: Application Of the Theoretical Model Of Ca 2 +-Dependent Regsupporting

confidence: 88%

Regulation of passive potassium transport of normal and transformed 3T3 mouse cell cultures by external calcium concentration and temperature

Ernst

Adam

1981

J. Membrain Biol.

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“…Asymmetrical conductances have been attributed to such effects on antibiotic ionophores (Ehrenstein & Lecar, 1977), toxins (Finkelstein, Rubin & Tzeng, 1976;Schein, Kagan & Finkelstein, 1978;Blumenthal & Klausner, 1982), lipids (McLaughlin & Harary, 1974), cellular transport molecules (Schein, Colombini & Finkelstein, 1976;Blumenthal & Shamoo, 1979), immune cytotoxic factors (Henkart & Blumenthal, 1975;Michaels, Abramovitz, Hammer & Mayer, 1976), and "gating" components of the sodium and potassium channels of nerve (Hodgkin & Huxley, 1952;Miller & Rosenberg, 1979).…”

Section: The Asymmetry Of Membrane Proteinsmentioning

confidence: 99%

Charge clusters and the orientation of membrane proteins

et al. 1982

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Summary.Although hydrophobic forces probably dominate in determining whether or not a protein will insert into a membrane, recent studies in our laboratory suggest that electrostatic forces may influence the final orientation of the inserted protein.A negatively charged hepatic receptor protein was found to respond to trans-positive membrane potentials as though "electrophoresing" into the bilayer. In the presence of ligand, the protein appeared to cross the membrane and expose binding sites on the opposite side. Similarly, a positively charged portion of the peptide melittin crosses a lipid membrane reversibly in response to a trans-negative potential. These findings, and others by Date and co-workers, have led us to postulate that transmembrane proteins would have hydrophobic transmembrane segments bracketed by positively charged residues on the cytoplasmic side and negatively charged residues on the extra-cytoplasmic side. In the thermodynamic sense, these asymmetrically placed charge clusters would create a compelling preference for correct orientation of the protein, given the inside-negative potential of most or all cells. This prediction is borne out by examination of the few transmembrane proteins (glycophorin, M13 coat protein, H-2K b, HLA-A2, HLA-B7, and mouse Igff heavy chain) for which we have sufficient information on both sequence and orientation.In addition to the usual diffusion and pump potentials measurable with electrodes, the ,microscopic" membrane potential reflects surface charge effects. Asymmetries in surface charge arising from either ionic or lipid asymmetries would be expected to enhance the bias for correct protein orientation, at least with respect to plasma membranes. We introduce a generalized form of Stern equation to assess surface charge and binding effects quantitatively. In the kinetic sense, dipole potentials within the membrane would tend to prevent positively charged residues from crossing the membrane to leave the cytoplasm. These considerations are consistent with the observed protein orientations. Finally, the electrostatic and hydrophobic factors noted here are combined in two hypothetical models of translocation, the first involving initial interaction of the presumptive transmembrane segment with the membrane; the second assuming initial interaction of a leader sequence.Key words membrane proteins 9 membrane biosynthesis 9 membrane potential -surface potential -surface charge -dipole potential 9 amino acid sequence

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“…Any two could be chosen and, because the membrane is asymmetric in its response to sodium ions, two is the minimum number. Biological membranes are generally asymmetric in their lipid and protein make-up (Bergelson & Barsukov, 1977 ;Rothman & Lenard, 1977) and also in the amount of surface change at the two aqueous/membrane interfaces (McLaughlin & Harary, 1974). The two membrane constants could be a and b, the willingness of the membrane to accept sodium from its two sides, or P, the membrane permeability, and b/a, a measure of the membrane asymmetry.…”

Section: I= -P(co-ci) F+ (Aco + Bci) Fvmentioning

confidence: 99%

Effects of internal and external sodium on the sodium current-voltage relationship in thesquid giant axon

Landowne

Scruggs

1981

J. Membrain Biol.

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The early transient current-voltage relationship was measured in internally perfused voltage clamped squid giant axons with various concentrations of sodium on the two sides of the membrane. In the absence of sodium on either side there is an outward transient current which is blocked by tetrodotoxin and varies with internal potassium concentration. The current increases linearly with voltage for positive potentials. Adding sodium ions internally increases the slope of the current-voltage relationship. Adding sodium ions externally also increases the slope between +10 and +80 mV. Adding sodium to both sides produces the sum of the two effects. The current-voltage relationships were fit by straight lines between +10 and +80 mV. Plotting the extrapolated intercepts with the current axis against the differences in sodium concentrations gave a straight line, Io = -P (Co-Ci)F. P, the Fickian permeability, is about 10(-4) cm/sec. Plotting the slopes in three dimensions against the two sodium concentrations gave a plane g = go + (aNao + bNai)F. a is about 10(-6) cm/mV-sec and b about 3 x 10(-6) cm/mV-sec. Thus the current-voltage relationship for the sodium current is well described by I = -P(Co-Ci)F+ (aco + bci)FV for positive potentials. This is the linear sum of Fick's Law and Ohm's Law. P/(a + b) = 25 +/- 1 mV (N = 6) and did not vary with the absolute magnitude of the currents. Within experimental error this is equal to kT/e or RT/F. Increasing temperature increased P, a and b proportionately. Adding external calcium, lithium, or Tris selectively decreased P and a without changing b. In the absence of sodium, altering internal and external potassium while observing the early transient currents suggests this channel is more asymmetric in its response to potassium than to sodium.

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Phospholipid Flip-Flop and the Distribution of Surface Charges in Excitable Membranes

Cited by 71 publications

References 11 publications

Regulation of passive potassium transport of normal and transformed 3T3 mouse cell cultures by external calcium concentration and temperature

Regulation of passive potassium transport of normal and transformed 3T3 mouse cell cultures by external calcium concentration and temperature

Charge clusters and the orientation of membrane proteins

Effects of internal and external sodium on the sodium current-voltage relationship in thesquid giant axon

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