Opinion Article published: 24 August 2010 doi: 10.3389/fphys.2010.00023 Membrane physiology and biophysics in the next decade: an open balcony to multiple scenarios
Mario L. Díaz*
Universidad de La Laguna, Tenerife, Spain *Correspondence: [email protected]
No doubt the cell membrane represents is becoming fainter. As an example, the ClC abnormal forms and processing of proteins the first evolutionary milestone in the family of ion channels shows an unusu- that are generated during the development construction of life. The basic structure ally broad variety of functional behaviors, of disease; this will certainly aid the design of primitive membranes likely provided a as some members work as gated chloride of appropriate therapeutic strategies. rather simple barrier to isolate an intra- channels and others as secondary chloride The complexity of the membrane sce- cellular compartment, where molecular transporters, for instance ClC-4 and ClC-5 nario is even more puzzling when it is real- “protobricks” started (assisted or not) to anion channels may be Cl-/H+-exchangers ized that non-cognate molecules physically develop life, a process that lasted around (Jentsch, 2008). Some other ion channels, associate with it. This is the case of canonical a 1000 million years. However, membrane like the voltage-dependent anion channels steroid receptors, such estrogen or proges- entities dramatically changed upon evolu- characteristic of mitochondrial outer mem- terone receptors that, though lacking alpha tion of metazoans, paralleling the appear- brane but also present at the plasma mem- helix domains, appear to be tightly inte- ance of differentiated tissues and organs. brane, can exhibit different conductance grated and immunoprecipitate with pro- In modern organisms, the differences in states with very different permeabilities. totypical membrane proteins, i.e., caveolin, cell membrane composition reflect neatly This channel is permeable to anions, includ- in purified plasma membranes. The inter- these evolutionary changes: supporting ing bulky anionic metabolites (such as ATP) esting point around this association is that specialized functions, and acquiring more in the largest conductance open state, but their activation by cognate ligands triggers and more molecular complexity as cells behaves as a cation-selective channel in the intracellular signals that largely differ from within tissues and organs became more and closed state. In addition, it can also function their classical transcriptional activities, more specialized. Countless symphonies in as a membrane-bound redox enzyme under which have given rise to a new concept on animal cell life rely on plasma membrane specific conditions (Shoshan-Barmatz et al., steroid transduction “Membrane-initiated composition and integrity, and examples 2010). The present panorama with ion steroid signaling” (Nemere et al., 2003). of membrane adaptation to enable physi- channels is certainly complex and requires Nonetheless, despite considerable molecu- ological adaptation to different physical extensive (re)investigation. lar evidence demonstrating the widespread environments are spectacular (Hazel and One of the most stimulating issues in nature of this phenomenon, the physiologi- Williams, 1990). the study of cell membrane is the number cal relevance of this observation at normal The development of high-resolution of human and animal pathologies that are circulating levels of steroids is extremely electrophysiological techniques in the 1980’s linked to alterations in discrete membrane limited, and much work is still to be done. has opened a revolutionary window for components, these including ion channels, Sophisticated imaging techniques, such the study and comprehension of ion chan- hormone and neurotransmitter recep- as confocal microscopy, TIRF (Total Internal nels, allowing the unprecedented real-time tors, transporters, membrane-associated Reflection Fluorescence), FRET (Förster observation of single protein molecules in enzymes and membrane lipids. The spec- resonance energy transfer) or multiphoton action. The discovery of the patch-clamp trum of these diseases encompasses a wide laser scanning microscopy have been devel- technique represented a real milestone and range of examples that extend from cystic oped in the last decades to study membrane gave rise to a frenzied scientific renaissance. fibrosis to long QT syndrome, from neph- biology in living cells, and the results have Nearly at the same time, the sophistication rolithiasis to hypertension, and from malig- undoubtedly revealed that cell membranes of molecular biology techniques allowed nant hyperthermia to neurodegeneration. are highly dynamic structures experienc- the cloning of the first ion channels, the Defects in membrane components have ing a continuous dialog and crosstalk with voltage-dependent sodium channel and the received considerable attention in the last intracellular membranes and the cytoskel- nicotinic acetylcholine receptor, both from several years and, to some extent, part of eton. The most recent research shows that Torpedo californica (Numa, 1986). Since these defects can be explained by mutated cell membranes are by far different from then our current understanding on how or altered membrane proteins. Yet, in many homogeneous as initially proposed by ion channels work and their contribution other cases, the biochemical defects can not Singer and Nicolson (1972), but consisting to physiological functions has increased be proven to be genetically derived, but of complex mosaics of different microdo- enormously. However, the answers to those rather are associated with abnormal protein mains, each containing different clusters of former questions have given birth to new processing, folding, association or altered proteins and lipids, that segregates laterally enigmas, i.e., ion channels are not that dif- protein trafficking toward the membrane within the vast sea of plasma membrane. At ferent from ion transporters, and the clear (Kass, 2005). Therefore, it is vital that we least some of these domains, namely lipid functional separation between both entities further our understanding of the various rafts, are known to function as signaling
www.frontiersin.org August 2010 | Volume 1 | Article 23 | 1 Díaz New challenges in membrane physiology
platforms involved in cellular commu- alternative methods are needed to allow In conclusion, the impressive research nication and transduction. What causes proteomic applications, mainly gel-based and knowledge accumulated in the last dec- this segregation and what mechanisms are analyses and mass spectrometry (Rabilloud, ades in the field of membrane physiology responsible for maintaining this topologi- 2009). Proteomic analysis of membrane and biophysics have uniquely positioned us cal organization under physiological con- proteins is a promising approach for the to explore the multiple facets of cell mem- ditions is a matter of intense investigation identification of novel drug targets and brane functions in health and disease. It is and represents a central challenge for the disease biomarkers. In the search for novel fascinating to realize how a few nanometers comprehension of membrane function. membrane proteins, analysis of protein of life can hold such enormous entropy. It is Plasma membranes not only exhibit hori- sequences using computational and bioin- the grand challenge of this specialty journal zontal heterogeneity, but also display transbi- formatic tools will allow for the prediction of to integrate all this information in the puz- layer asymmetry. This is obvious for extrinsic the presence of transmembrane integratable zle of cell biology in physiology and medi- membrane proteins, but what makes this domains. Along with technological innova- cine. Exciting times wait ahead. surprising is that it is also reflected in the tions in the foreseeable future, advances in distribution of membrane phospholipids the areas of sample preparation and com- References and cholesterol, which makes the inner leaflet putational prediction of membrane proteins Hazel, J. R., and Williams, E. E. (1990). The role of altera- of the bilayer different than that as seen from will lead to exciting discoveries. tions in membrane lipid composition in enabling physiological adaptation of organisms to their physi- the extracellular medium. At present, we have Another important issue in the field of cal environment. Prog. Lipid Res. 29, 167–227. only taken more or less detailed pictures of membrane physiology research is that we Jentsch, T. J. (2008). CLC chloride channels and transport- live cell membranes but the physiological need to understand protein-lipid interac- ers: from genes to protein structure, pathology and meanings of these structural complexities tions within membrane domains. It is known physiology. Crit. Rev. Biochem. Mol. Biol. 43, 3–36. remain mysterious. The observation that that, at least for some integral proteins, there Kass, R. S. (2005). The channelopathies: novel insights into molecular and genetic mechanisms of human membrane asymmetry is disrupted in some is an absolute requirement of a specific disease. J. Clin. Invest. 115, 1986–1989. human diseases, i.e., Alzheimer’s disease, microenvironment. In addition, peripheral Nemere, I., Pietras, R. J., and Blackmore, P. F. (2003). indicates that maintaining membrane struc- membrane proteins that contain hydropho- Membrane receptors for steroid hormones: signal ture is crucial for normal neuronal function. bic anchors, i.e., glycosylphosphatidylinosi- transduction and physiological significance. J. Cell. Biochem. 88, 438–445. We still need to explore the mechanisms that tol (GPI)-anchored proteins that penetrate Numa, S. (1986). Molecular basis for the function of ionic lead to these alterations, and their precise the interfacial region of the membrane in a channels. Biochem. Soc. Symp. 52, 119–143. involvement in the origin and progression domain specific manner need a particular Rabilloud, T. (2009). Membrane proteins and proteom- of the pathologies. lipid composition. Experimental evidence ics: love is possible, but so difficult. Electrophoresis One of the most important limita- indicates that alteration of the lipid envi- 30(Suppl. 1), S174–S180. Shoshan-Barmatz, V., De Pinto, V., Zweckstetter, M., tions in the comprehension of membrane ronment critically affects the thermody- Raviv, Z., Keinan, N., and Arbel, N. (2010). VDAC, protein structure-function relationship namic properties of membrane proteins, a multi-functional mitochondrial protein regulating emerges from the fact that, unlike cytosolic likely due to alteration of conformational cell life and death. Mol. Aspects Med. 31, 227–285. proteins, membrane-embedded proteins changes during the catalytic cycle of the Singer, S. J., and Nicolson, G. L. (1972). The fluid mosaic are not readily amenable to existing crys- particular protein. We obtained this knowl- model of the structure of cell membranes. Science 175, 720–731. tallization methods and only few protein edge, from ion channels reconstituted in structures have now been determined using liposomes: a particular phospholipid com- Received: 13 July 2010; accepted: 13 July 2010; published X-ray crystallography. This is due to the fact position determines a particular behavior. online: 24 August 2010. that membrane proteins require a balanced It is obvious then the necessity to combine Citation: Díaz ML (2010) Membrane physiology hydrophilic and lipophilic environment, information from biochemical, molecular and biophysics in the next decade: an open balcony to while most protein chemistry methods work physiology and biophysical approaches multiple scenarios. Front. Physio. 1:23. doi: 10.3389/ fphys.2010.00023 mainly in water-based media. There is an to achieve a real view on how proteins This article was submitted to Frontiers in Membrane urgent need for advances in technologies to and lipids interact at the plasma mem- Physiology and Biophysics, a specialty of Frontiers in generate structural and functional informa- brane and modulate membrane function. Physiology. tion for membrane proteins. Despite nota- Moreover, tackling these studies could help Copyright © 2010 Díaz. This is an open-access article subject to an exclusive license agreement between the authors and ble technological developments, obstacles us to gain knowledge on the cellular basis the Frontiers Research Foundation, which permits unre- related to extraction and solubilization of of membrane-associated pathologies that stricted use, distribution, and reproduction in any medium, membrane proteins is encountered, and lacks a known genetic background. provided the original authors and source are credited.
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