Unifying Electrostatic Mechanism for Receptor-Ligand Activity

Journal of Receptors and Signal Transduction

2008

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Previously, an electrostatic mechanism was proposed for receptor-ligand action and for cell signaling by phosphate and sulfate. The hypothesis is further elaborated by application to metal ions, mainly calcium, magnesium, zinc, iron, and copper, in receptors and cell signaling. Evidence is provided for involvement of electrostatics in various reaction modes in biosystems. Calcium plays an important role electrochemically in neurotransmission. In some cases, electron transfer and redox processes are also involved. Electrostatics are known to participate in plant biochemistry. Mechanistically, the electrostatic field may act as a conduit for electrons and radicals and in involvement with energetics.

Section: Quantitative Aspectsmentioning

confidence: 88%

“…Prior reviews advanced the proposal of function as a conduit for electrons and radicals (1)(2)(3). A 2006 report on photosynthesis mechanism furnishes strong support for electrostatic action that energetically facilitates electron migration (4).…”

Section: Role Of Electrostatic Forcesmentioning

confidence: 94%

Unifying Electrostatic Mechanism for Metal Cations in Receptors and Cell Signaling

Journal of Receptors and Signal Transduction

2008

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“…Some reports contain comments concerning lack 434 P. Kovacic, C. D. Draskovich, and R. S. Pozos of knowledge as to the mode of action. The hypothesis was advanced that the electrostatic field associated with the anion plays a role in the communication grid (2,3). In the case of sulfate, which has attracted less attention, a similar participation was proposed for the ionic species (3).…”

Section: Introductionmentioning

confidence: 96%

“…Recently, electrical effects were proposed to be involved in cell signaling (1) and receptor-ligand activity (2,3). In the receptor case, electrostatic fields introduced by ions and dipoles of the ligands are designated as important elements in the communication system.…”

Section: Introductionmentioning

confidence: 99%

Unifying Electrostatic Mechanism for Phosphates and Sulfates in Cell Signaling

Journal of Receptors and Signal Transduction

Draskovich

Pozos

2007

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Prior proposals suggested the importance of electrochemistry in signal transduction and receptor-ligand activity. Electrostatic fields associated with ions and dipoles were assigned important roles. Little is known concerning the precise mode of action in cell signaling by widespread phosphorylation. According to the hypothetical framework, molecular electrostatic potential associated with phosphate anion is a key element as a link in the communication grid, possibly inducing favorable energetics in the electron transfer process. Similar involvement appears plausible for the sulfate anion. Supporting evidence for the electrostatic mechanism is presented. Representative literature on phosphorylation in the biological domain is reviewed with emphasis on cell signaling. The treatment includes phosphates from protein, lipids, and other molecules, plus the role of reactive oxygen species. Protein sulfation is also discussed.

“…Subjects addressed are enzymes, membranes, chromosomes, histamine, receptors, the Hofmeister effect, plant chemistry and evolutionary development. A recent hypothesis proposes that electrostatic force is a factor in receptor-ligand action, based on the molecular electrostatic potential (MEP) associated with ions and dipoles 17. Energetics and bridging may be important actors.…”

Section: Introductionmentioning

confidence: 99%

Zolpidem, A Clinical Hypnotic that Affects Electronic Transfer, Alters Synaptic Activity Through Potential Gaba Receptors in the Nervous System Without Significant Free Radical Generation

Oxidative Medicine and Cellular Longevity

Somanathan

2009

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Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relationships (SAR) and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action.The pyridinium cation displays molecular electrostatic potential which may well play a role energetically or as a bridging mechanism. An SAR analysis points to analogy with other physiologically active xenobiotics, namely benzodiazepines and paraquat in the conjugated iminium category. Inactivity of metabolites indicates that the parent is the active form of zolpidem. Absence of reactive oxygen species and oxidative stress is in line with minor side effects. In contrast, generally, the prior literature contains essentially no discussion of these fundamental biochemical relationships. Pharmacodynamics may play an important role. Concerning behavior at the blood-brain barrier, useful insight can be gained from investigations of the related cationic anesthetics that are structurally related to acetyl choline. Evidently, the neutral form of the drug penetrates the neuronal membrane, with the salt form operating at the receptor. The pathways of zolpidem have several clinical implications since the agent affects sedation, electroencephalographic activity, oxidative metabolites and receptors in the central nervous system. The drug acts at the GABA(A) receptor benzodiazepine site, displaying high and intermediate affinities to various receptor regions. Structural features for tight binding were determined. The sedative and anticonvulsant activities are due to its action on the alpha-1-GABA(A) receptors. One of the common adverse responses to zolpidem is hallucinations. Proposed mechanisms comprise changes in the GABA(A) receptor, pharmacodynamic interactions involving serotonin and neuronal-weak photon emission processes entailing redox phenomena. Reports cite cases of abuse with cravings based on anxiolytic and stimulating actions. It is important to recognize that insight concerning processes at the fundamental, molecular level can translate into beneficial results involving both positive and adverse side effects. In order for this to occur, interdisciplinary interaction is necessary. Suggestions are made for future research aimed at testing the various hypotheses.