Membrane Crossover by Cell-Penetrating Peptides: Kinetics and Mechanisms – From Model to Cell Membrane Perturbation by Permeant Peptides - Intracellular Delivery: Fundamentals and Applications - page 191

the potential (Terrone et al. 2003 ). Modulation of membrane potential trough varia-
tion of potassium concentration outside Jurkat cells also showed a strong impact on
uptake of fluorescently labelled Tat49-57 or arginine octamer (Rothbard et al. 2004 ),
and of biotin-labelled RW9 (R6W3) (Delaroche et al. 2007 ). Thus, the role of the
potential in cell-penetrating peptide internalization needs to be included in transloca-
tion mechanisms. For example, in the frame of the hydrophobic counterion model,
the sensitivity of a CPP to the potential requires the absence of neutralization of cer-
tain positive charges as suggested by Rothbard and collaborators (Rothbard et al.
2004 ). Intriguingly, crossing the membrane for a positive elementary charge amounts
to a gain of ~5 kT for a -100 mV potential that appears at first sight weak compared
to the Born energy of the charge. For models that appeal to aqueous pore formation,
an obvious impact of the potential would be a proportional electromotive force on
charges in the pore that may be supplemented by a promoting effect on pore forma-
tion (the later is not seen on the linear I-V relationship of the ionic current generated
in a planar bilayer by arginine octamer in Herce et al. ( 2009 )).
This review of possible pathways for CPP translocation illustrates that direct
investigations of the mechanism are difficult because all mechanisms involve nano-
metric, rare, transient structures. However very significant progress has been
recently made in the understanding of the complex interactions between mem-
branes and CPPs and a clarification of the mechanisms of translocation is likely to
occur in upcoming years.
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