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Is electron-transfer from glutamate receptors or other plasma membrane ionic channels involved in oxidative stress and neurodegenerative diseases?
Medical Hypotheses (1996)46, 303-304
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Is Electron-Transfer from Glutamate Receptors or Other Plasma Membrane Ionic Channels Involved in Oxidative Stress and Neurodegenerative Diseases? G. CAVELIER Visiting Research Scientist, Yale University School of Medicine, Department of Cellular and Molecular Physiology, 333 Cedar Street, New Haven, CT 06510, USA (Correspondence to: German Cavelier MS, Professor, Department of Electrical Engineering, Universidad de Los Andes, AA 4976, Santafe de Bogota, Colombia. Te# (57) (1) 286 6436; Fax: (57) (1) 284 1570)
Abstract - - There is theoretical evidence that biopolymers such as proteins can have semiconductor properties, with electrons (and holes) that can move inside the macromolecule. Double layers of charge can thus be formed at the plasma membrane protein interface with the electrolytes. Electron-transfer can occur at such interfaces too, and electrons can participate in charge transport processes across the biopolymer from one side of the plasma membrane to the other. These phenomena are studied here in the pathological case when the average equilibrium in the electron-transfer process at the cytoplasmic interface suffers a continued offset that leads to free-radical formation inside the cell. This would help in the long term to increase oxidative stress inside the cell, and would thus contribute to the appearance of neurodegenerative diseases.
The study of the electronic structure and interfacial phenomena in plasma membrane proteins shows that free electrons could be participating in several features of their function. One possibility examined here more closely is that, under certain pathological conditions, there could be electrons leaking from these (otherwise normal) plasma membrane receptors or ionic channels to the cytoplasm. This electron leakage could be one of the causes of oxidative stress, a condition that has been associated with a number of diseases, among them several neurodegenerative diseases.
There is theoretical evidence (1) that in biopolymers like proteins and DNA there can be a band structure like in inorganic semiconductors, whereby electrons and holes can move inside such biopolymers. Therefore, the electrons and holes could participate in spatial accumulation (or depletion) of charge in the macromolecule, mainly at the interfaces; they could also participate in transport processes (1) (mainly by hopping) through it. One might thus expect at the polymer end surfaces an accumulation or depletion of such charges (space charge), intimately related to the interface potentials (double layer) (2).
Date received20 June 1995 Date accepted26 June 1995 303
304 Given this interface configuration, one might also expect that under the appropriate conditions (electrochemical potential difference) there can be an electron transfer (3) current at the interface, to or from one of such biopolymers, to another biopolymer or to a foreign electron donor/acceptor molecule that approaches, adsorbs, or binds the biopolymer. This charge transfer may establish a reorganization of the interface charges and potentials, as well as a change in the local electrostatic forces involved (4). In this way, the electrons might be involved in modulating the conformational changes of the plasma membrane receptors and ionic channels upon binding or adsorption of the effectors on them (neurotransmitters, G proteins, and other neuromodulators). The foregoing analysis can be applied to the plasma membrane receptors and ionic channels as described above, in a number of cases related to modulation of their function (5). However, it is also of interest to consider the possibility that the electron-transfer process can be followed by an electron transport through the plasma membrane protein, for example from the outside interface to the inside. Thereafter, the electrons could be injected by the concentration gradient into the intracellular electrolyte. Alternatively, electrons (holes) can be transferred from the space charge at the internal interface of the protein, to the cytoplasmic electrolyte under appropriate conditions (for example a local overpotential). At this point, an additional possibility is that the injected electrons (holes) participate in the formation of free radicals, in the cytoplasmic vicinity of the plasma membrane protein. Of course, the reverse reaction is possible, and there can be, in the long term, an overall equilibrium, with very few free radicals escaping from the vicinity of the electrolyte-protein interface, being soon eliminated by the reverse reaction, or by one of the protective mechanisms (scavengers) that the cell has against free radicals (6). Now, what would happen if the particular plasma membrane receptor or ionic channel has a mutation or malfunctioning (7) that does not appreciably affect its physiological function, but that by an excessive cytoplasmic injection of electrons (holes) creates a nonequilibrium in the process of free radical formation/ elimination? The result would be an accumulation of free radicals inside the cell that can overwhelm the protective mechanisms that the cell has against free radicals. In this way, the non-equilibrium situation described can cause oxidative stress inside the cell. Oxidative stress has been linked to a number of
MEDICAL HYPOTHESES
neurodegenerative diseases, with increasing additional evidence that stimulation of the glutamate receptors and the production of oxidative stress are sequential and interacting processes that lead to such neurodegenerative diseases (6-8). Thus, another of the causes of the non-equilibrium situation described above could be the excessive stimulation of the glutamate receptors, giving an additional path to oxidative stress and neurodegeneration. In this way, if a faulty plasma membrane receptor or ion channel (faulty in the sense of causing a nonequilibrium in the free radical formation/elimination process, but otherwise physiologically normal) functions in those conditions for a long time, it will create and maintain, in the long term, oxidative stress inside the cell, and so this faulty receptor or ionic channel could be one of the causes of the neurodegenerative diseases that have been associated with the existence of such oxidative stress.
Acknowledgements This research was supported in part by Fellowships from the Organization of American States, Washington DC, COLCIENCIAS (Colombian Institute for Science and Technology) and Universidad de Los Andes, Santafe de Bogota, Colombia. The author is grateful for the kind hospitality and collaboration of the laboratory of Dr Fred Sigworth, Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
References 1. Ladik J J. Periodic biopolymers; transport properties of polymers. In: Ladik J J, ed. Quantum Theory of Polymers as Solids. New York: Plenum Press, 1988: 74-84; 323-357. 2. Boekris J O M, Khan S U M. The semiconductor-solution interface. In: Bockris, J O M, Khan S U M, eds. Surface Electrochemistry: A Molecular Level Approach. New York: Plenum Press, 1993: 167-188. 3. Marcus R A, Sutin N. Electron transfers in chemistry and biology. Biochim Biophys Acta 1985; 811: 265-322. 4. Ladik J J. Electronic structure of biopolymers. In: Andre J-M, Delhalle J, Ladik, J J, eds. Quantum Theory of Polymers. Boston: Dordrecht-Reidel, 1978: 257-278. 5. Cavelier G. Short note: are electron-transport and electrontransfer involved in intracellular signaling? Med Hypotheses 1995; 44 (4): 261-262. 6. Coyle J T, Putlfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993; 262: 689-695. 7. Olanow C W. A radical hypothesis for neurodegeneration. Trends Neurosci 1993; 16(11): 439 444. 8. Lipton S A. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci 1993; 16(12): 527-532.
© PearsonProfessionalLtd 1996
Is Electron-Transfer from Glutamate Receptors or Other Plasma Membrane Ionic Channels Involved in Oxidative Stress and Neurodegenerative Diseases? G. CAVELIER Visiting Research Scientist, Yale University School of Medicine, Department of Cellular and Molecular Physiology, 333 Cedar Street, New Haven, CT 06510, USA (Correspondence to: German Cavelier MS, Professor, Department of Electrical Engineering, Universidad de Los Andes, AA 4976, Santafe de Bogota, Colombia. Te# (57) (1) 286 6436; Fax: (57) (1) 284 1570)
Abstract - - There is theoretical evidence that biopolymers such as proteins can have semiconductor properties, with electrons (and holes) that can move inside the macromolecule. Double layers of charge can thus be formed at the plasma membrane protein interface with the electrolytes. Electron-transfer can occur at such interfaces too, and electrons can participate in charge transport processes across the biopolymer from one side of the plasma membrane to the other. These phenomena are studied here in the pathological case when the average equilibrium in the electron-transfer process at the cytoplasmic interface suffers a continued offset that leads to free-radical formation inside the cell. This would help in the long term to increase oxidative stress inside the cell, and would thus contribute to the appearance of neurodegenerative diseases.
The study of the electronic structure and interfacial phenomena in plasma membrane proteins shows that free electrons could be participating in several features of their function. One possibility examined here more closely is that, under certain pathological conditions, there could be electrons leaking from these (otherwise normal) plasma membrane receptors or ionic channels to the cytoplasm. This electron leakage could be one of the causes of oxidative stress, a condition that has been associated with a number of diseases, among them several neurodegenerative diseases.
There is theoretical evidence (1) that in biopolymers like proteins and DNA there can be a band structure like in inorganic semiconductors, whereby electrons and holes can move inside such biopolymers. Therefore, the electrons and holes could participate in spatial accumulation (or depletion) of charge in the macromolecule, mainly at the interfaces; they could also participate in transport processes (1) (mainly by hopping) through it. One might thus expect at the polymer end surfaces an accumulation or depletion of such charges (space charge), intimately related to the interface potentials (double layer) (2).
Date received20 June 1995 Date accepted26 June 1995 303
304 Given this interface configuration, one might also expect that under the appropriate conditions (electrochemical potential difference) there can be an electron transfer (3) current at the interface, to or from one of such biopolymers, to another biopolymer or to a foreign electron donor/acceptor molecule that approaches, adsorbs, or binds the biopolymer. This charge transfer may establish a reorganization of the interface charges and potentials, as well as a change in the local electrostatic forces involved (4). In this way, the electrons might be involved in modulating the conformational changes of the plasma membrane receptors and ionic channels upon binding or adsorption of the effectors on them (neurotransmitters, G proteins, and other neuromodulators). The foregoing analysis can be applied to the plasma membrane receptors and ionic channels as described above, in a number of cases related to modulation of their function (5). However, it is also of interest to consider the possibility that the electron-transfer process can be followed by an electron transport through the plasma membrane protein, for example from the outside interface to the inside. Thereafter, the electrons could be injected by the concentration gradient into the intracellular electrolyte. Alternatively, electrons (holes) can be transferred from the space charge at the internal interface of the protein, to the cytoplasmic electrolyte under appropriate conditions (for example a local overpotential). At this point, an additional possibility is that the injected electrons (holes) participate in the formation of free radicals, in the cytoplasmic vicinity of the plasma membrane protein. Of course, the reverse reaction is possible, and there can be, in the long term, an overall equilibrium, with very few free radicals escaping from the vicinity of the electrolyte-protein interface, being soon eliminated by the reverse reaction, or by one of the protective mechanisms (scavengers) that the cell has against free radicals (6). Now, what would happen if the particular plasma membrane receptor or ionic channel has a mutation or malfunctioning (7) that does not appreciably affect its physiological function, but that by an excessive cytoplasmic injection of electrons (holes) creates a nonequilibrium in the process of free radical formation/ elimination? The result would be an accumulation of free radicals inside the cell that can overwhelm the protective mechanisms that the cell has against free radicals. In this way, the non-equilibrium situation described can cause oxidative stress inside the cell. Oxidative stress has been linked to a number of
MEDICAL HYPOTHESES
neurodegenerative diseases, with increasing additional evidence that stimulation of the glutamate receptors and the production of oxidative stress are sequential and interacting processes that lead to such neurodegenerative diseases (6-8). Thus, another of the causes of the non-equilibrium situation described above could be the excessive stimulation of the glutamate receptors, giving an additional path to oxidative stress and neurodegeneration. In this way, if a faulty plasma membrane receptor or ion channel (faulty in the sense of causing a nonequilibrium in the free radical formation/elimination process, but otherwise physiologically normal) functions in those conditions for a long time, it will create and maintain, in the long term, oxidative stress inside the cell, and so this faulty receptor or ionic channel could be one of the causes of the neurodegenerative diseases that have been associated with the existence of such oxidative stress.
Acknowledgements This research was supported in part by Fellowships from the Organization of American States, Washington DC, COLCIENCIAS (Colombian Institute for Science and Technology) and Universidad de Los Andes, Santafe de Bogota, Colombia. The author is grateful for the kind hospitality and collaboration of the laboratory of Dr Fred Sigworth, Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
References 1. Ladik J J. Periodic biopolymers; transport properties of polymers. In: Ladik J J, ed. Quantum Theory of Polymers as Solids. New York: Plenum Press, 1988: 74-84; 323-357. 2. Boekris J O M, Khan S U M. The semiconductor-solution interface. In: Bockris, J O M, Khan S U M, eds. Surface Electrochemistry: A Molecular Level Approach. New York: Plenum Press, 1993: 167-188. 3. Marcus R A, Sutin N. Electron transfers in chemistry and biology. Biochim Biophys Acta 1985; 811: 265-322. 4. Ladik J J. Electronic structure of biopolymers. In: Andre J-M, Delhalle J, Ladik, J J, eds. Quantum Theory of Polymers. Boston: Dordrecht-Reidel, 1978: 257-278. 5. Cavelier G. Short note: are electron-transport and electrontransfer involved in intracellular signaling? Med Hypotheses 1995; 44 (4): 261-262. 6. Coyle J T, Putlfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993; 262: 689-695. 7. Olanow C W. A radical hypothesis for neurodegeneration. Trends Neurosci 1993; 16(11): 439 444. 8. Lipton S A. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci 1993; 16(12): 527-532.