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Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists. [ABSTRACT FROM AUTHOR]

What triggers type 1 diabetes mellitus (T1DM)? One common assumption is that triggers are individual microbes that mimic autoantibody targets such as insulin (INS). However, most microbes highly associated with T1DM pathogenesis, such as coxsackieviruses (COX), lack INS mimicry and have failed to induce T1DM in animal models. Using proteomic similarity search techniques, we found that COX actually mimicked the INS receptor (INSR). Clostridia were the best mimics of INS. Clostridia antibodies cross-reacted with INS in ELISA experiments, confirming mimicry. COX antibodies cross-reacted with INSR. Clostridia antibodies further bound to COX antibodies as idiotype–anti-idiotype pairs conserving INS–INSR complementarity. Ultraviolet spectrometry studies demonstrated that INS-like Clostridia peptides bound to INSR-like COX peptides. These complementary peptides were also recognized as antigens by T cell receptor sequences derived from T1DM patients. Finally, most sera from T1DM patients bound strongly to inactivated Clostridium sporogenes, while most sera from healthy individuals did not; T1DM sera also exhibited evidence of anti-idiotype antibodies against idiotypic INS, glutamic acid decarboxylase, and protein tyrosine phosphatase non-receptor (islet antigen-2) antibodies. These results suggest that T1DM is triggered by combined enterovirus-Clostridium (and possibly combined Epstein–Barr-virus-Streptococcal) infections, and the probable rate of such co-infections approximates the rate of new T1DM diagnoses. [ABSTRACT FROM AUTHOR]

The standard approach to exploring prebiotic chemistry is to use a small number of highly purified reactants and to attempt to optimize the conditions required to produce a particular end product. However, purified reactants do not exist in nature. We have previously proposed that what drives prebiotic evolution are complex chemical ecologies. Therefore, we have begun to explore what happens if one substitutes "sea water", with its complex mix of minerals and salts, for distilled water in the classic Miller experiment. We have also adapted the apparatus to permit it to be regassed at regular intervals so as to maintain a relatively constant supply of methane, hydrogen, and ammonia. The "sea water" used in the experiments was created from Mediterranean Sea salt with the addition of calcium phosphate and magnesium sulfate. Tests included several types of mass spectrometry, an ATP-monitoring device capable of measuring femtomoles of ATP, and a high-sensitivity cAMP enzyme-linked immunoadsorption assay. As expected, amino acids appeared within a few days of the start of the experiment and accumulated thereafter. Sugars, including glucose and ribose, followed as did long-chain fatty acids (up to C20). At three-to-five weeks after starting the experiment, ATP was repeatedly detected. Thus, we have shown that it is possible to produce a "one-pot synthesis" of most of the key chemical prerequisites for living systems within weeks by mimicking more closely the complexity of real-world chemical ecologies. [ABSTRACT FROM AUTHOR]

Opioids and their antagonists alter vitamin C metabolism. Morphine binds to glutathione (l-γ-glutamyl-l-cysteinyl-glycine), an intracellular ascorbic acid recycling molecule with a wide range of additional activities. The morphine metabolite morphinone reacts with glutathione to form a covalent adduct that is then excreted in urine. Morphine also binds to adrenergic and histaminergic receptors in their extracellular loop regions, enhancing aminergic agonist activity. The first and second extracellular loops of adrenergic and histaminergic receptors are, like glutathione, characterized by the presence of cysteines and/or methionines, and recycle ascorbic acid with similar efficiency. Conversely, adrenergic drugs bind to extracellular loops of opioid receptors, enhancing their activity. These observations suggest functional interactions among opioids and amines, their receptors, and glutathione. We therefore explored the relative binding affinities of ascorbic acid, dehydroascorbic acid, opioid and adrenergic compounds, as well as various control compounds, to glutathione and glutathione-like peptides derived from the extracellular loop regions of the human beta 2-adrenergic, dopamine D1, histamine H1, and mu opioid receptors, as well as controls. Some cysteine-containing peptides derived from these receptors do bind ascorbic acid and/or dehydroascorbic acid and the same peptides generally bind opioid compounds. Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin. Some adrenergic drugs also bind to glutathione and glutathione-like receptor regions. These sets of interactions provide a novel basis for understanding some ways that adrenergic, opioid and antioxidant systems interact during anesthesia and drug abuse and may have utility for understanding drug interactions. [ABSTRACT FROM AUTHOR]

Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action. [ABSTRACT FROM AUTHOR]