title: Sodium selective ion channel formation in living cell membranes by polyamidoamine dendrimer.
abstract: Polyamidoamine (PAMAM) dendrimers are highly charged hyperbranched protein-like polymers that are known to interact with cell membranes. In order to disclose the mechanisms of dendrimer-membrane interaction, we monitored the effect of PAMAM generation five (G5) dendrimer on the membrane permeability of living neuronal cells followed by exploring the underlying structural changes with infrared-visible sum frequency vibrational spectroscopy (SVFS), small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). G5 dendrimers were demonstrated to irreversibly increase the membrane permeability of neurons that could be blocked in low-[Na(+)], but not in low-[Ca(2+)] media suggesting the formation of specific Na(+) permeable channels. SFVS measurements on silica supported DPPG-DPPC bilayers suggested G5-specific trans-polarization of the membrane. SAXS data and freeze-fracture TEM imaging of self-organized DPPC vesicle systems demonstrated disruption of DPPC vesicle layers by G5 through polar interactions between G5 terminal amino groups and the anionic head groups of DPPC. We propose a nanoscale mechanism by which G5 incorporates into the membrane through multiple polar interactions that disrupt proximate membrane bilayer and shape a unique hydrophilic Na(+) ion permeable channel around the dendrimer. In addition, we tested whether these artificial Na(+) channels can be exploited as antibiotic tools. We showed that G5 quickly arrest the growth of resistant bacterial strains below 10μg/ml concentration, while they show no detrimental effect on red blood cell viability, offering the chance for the development of new generation anti-resistant antibiotics.
authors.affiliation: Department of Functional Pharmacology, Hungarian Academy of Sciences, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nyitrai
authors.forename: Tamás
authors.initials: T
authors.lastname: Keszthelyi
authors.forename: Attila
authors.initials: A
authors.lastname: Bóta
authors.forename: Agnes
authors.initials: A
authors.lastname: Simon
authors.forename: Orsolya
authors.initials: O
authors.lastname: Tőke
authors.forename: Gergő
authors.initials: G
authors.lastname: Horváth
authors.forename: Ildikó
authors.initials: I
authors.lastname: Pál
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
authors.forename: László
authors.initials: L
authors.lastname: Héja
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000737:chemistry / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D013057:Spectrum Analysis
chemical_list: D050091:Dendrimers; D008051:Lipid Bilayers; C531249:Poly(amidoamine); D011073:Polyamines; D015222:Sodium Channels; D012964:Sodium