Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects

Tokarska-Schlattner, Malgorzata; Epand, Raquel F.; Meiler, Flurina; Zandomeneghi, Giorgia; Neumann, Dietbert; Widmer, Hans R.; Meier, Beat H.; Epand, Richard M.; Saks, Valdur; Wallimann, Theo; Schlattner, Uwe (2012). Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects. PLoS ONE, 7(8), e43178. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0043178

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A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr) and their cyclic analogues cyclo-(cCr) and phospho-cyclocreatine (PcCr). Cr is widely used as nutritional supplement in sports and increasingly also as adjuvant treatment for pathologies such as myopathies and a plethora of neurodegenerative diseases. Additionally, Cr and its cyclic analogues have been proposed for anti-cancer treatment. The mechanisms involved in these pleiotropic effects are still controversial and far from being understood. The reversible conversion of Cr and ATP into PCr and ADP by creatine kinase, generating highly diffusible PCr energy reserves, is certainly an important element. However, some protective effects of Cr and analogues cannot be satisfactorily explained solely by effects on the cellular energy state. Here we used mainly liposome model systems to provide evidence for interaction of PCr and PcCr with different zwitterionic phospholipids by applying four independent, complementary biochemical and biophysical assays: (i) chemical binding assay, (ii) surface plasmon resonance spectroscopy (SPR), (iii) solid-state (31)P-NMR, and (iv) differential scanning calorimetry (DSC). SPR revealed low affinity PCr/phospholipid interaction that additionally induced changes in liposome shape as indicated by NMR and SPR. Additionally, DSC revealed evidence for membrane packing effects by PCr, as seen by altered lipid phase transition. Finally, PCr efficiently protected against membrane permeabilization in two different model systems: liposome-permeabilization by the membrane-active peptide melittin, and erythrocyte hemolysis by the oxidative drug doxorubicin, hypoosmotic stress or the mild detergent saponin. These findings suggest a new molecular basis for non-energy related functions of PCr and its cyclic analogue. PCr/phospholipid interaction and alteration of membrane structure may not only protect cellular membranes against various insults, but could have more general implications for many physiological membrane-related functions that are relevant for health and disease.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurosurgery

UniBE Contributor:

Widmer, Hans Rudolf

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:37

Last Modified:

27 Dec 2014 23:45

Publisher DOI:

10.1371/journal.pone.0043178

PubMed ID:

22912820

Web of Science ID:

000308063700056

BORIS DOI:

10.7892/boris.14891

URI:

https://boris.unibe.ch/id/eprint/14891 (FactScience: 222030)

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