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8.A.39 The Homeobox; Penetratin (Penetratin) Family

Calcium-activated chloride currents (CaCCs) are required for epithelial electrolyte and fluid secretion, fertilization, sensory transduction and excitability of neurons and smooth muscle. Defolliculated Xenopus oocytes express a robust CaCC formed by a heterologous group of proteins including transmembrane protein 16A (TMEM16A) and bestrophins. Penetratin, a 16-amino acid peptide, potentiates endogenous oocyte CaCCs by ~50-fold at 10 μM. CaCC potentiation was rapid and dose-dependent (EC50=3.2 μM). Penetratin-potentiated currents reversed at -18 mV and were dependent on the extracellular divalent cations present, showing positive regulation by Ca2+ and Mg2+ but effective block by Zn2+ (IC50=5.9 μM). Extracellular Cd2+, Cu2+ and Ba2+ resulted in bimodal responses: CaCC inhibition at low but potentiation at high concentrations. Intracellular BAPTA injection, which prevents activation of CaCCs, and the Cl- channel blockers niflumic acid and DIDS, significantly reduced potentiation. In contrast, the K+ channel blockers Cs+, TEA, tertiapin-Q and halothane had no effect. This pharmacological profile is consistent with penetratin potentiation of zinc-sensitive CaCCs that are activated by influx of extracellular Ca2+ (Kanjhan and Bellingham, 2011; Durzyńska et al. 2015).

Cell penetrating peptides (CPPs) are small peptides that are able to penetrate the plasma membranes of mammalian cells. Because these peptides can also carry large hydrophilic cargos such as proteins, they could potentially be used to transport biologically active drugs across cell membranes. One characteristic feature of the CPPs is that they typically have a net positive charge. Therefore, a key issue associated with the transport mechanism is the role of the transmembrane electrochemical potential in driving the peptides across the membrane. Björklund et al. 2006 reconstituted bacteriorhodopsin (bR) in large unilamellar vesicles (LUVs) with fluorescein-labeled CPP penetratin enclosed within the LUVs under conditions when the fluorescence is quenched. Illumination of the bacteriorhodopsin-containing LUVs resulted in creation of a transmembrane proton electrochemical gradient (positive on the inside). Upon generation of this gradient, an increase in fluorescence was observed, showing that the proton gradient drives the translocation of penetratin (Björklund et al. 2006).

References associated with 8.A.39 family:

Batta, G., L. Kárpáti, G.F. Henrique, G. Tóth, S. Tarapcsák, T. Kovács, F. Zákány, I.M. Mándity, and P. Nagy. (2021). Statin-boosted cellular uptake and endosomal escape of penetratin due to reduced membrane dipole potential. Br J Pharmacol. [Epub: Ahead of Print] 33908640
Björklund, J., H. Biverståhl, A. Gräslund, L. Mäler, and P. Brzezinski. (2006). Real-time transmembrane translocation of penetratin driven by light-generated proton pumping. Biophys. J. 91: L29-31. 16782795
Durzyńska, J., &.#.3.2.1.;. Przysiecka, R. Nawrot, J. Barylski, G. Nowicki, A. Warowicka, O. Musidlak, and A. Goździcka-Józefiak. (2015). Viral and other cell-penetrating peptides as vectors of therapeutic agents in medicine. J Pharmacol Exp Ther 354: 32-42. 25922342
Kanjhan, R. and M.C. Bellingham. (2011). Penetratin peptide potentiates endogenous calcium-activated chloride currents in Xenopus oocytes. J. Membr. Biol. 241: 21-29. 21442407
Pescina, S., C. Ostacolo, I.M. Gomez-Monterrey, M. Sala, A. Bertamino, F. Sonvico, C. Padula, P. Santi, A. Bianchera, and S. Nicoli. (2018). Cell penetrating peptides in ocular drug delivery: State of the art. J Control Release 284: 84-102. 29913221