Anna Carnini

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (6)28.9 Total impact

  • Source
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    ABSTRACT: Structural studies of polytopic membrane proteins are often hampered by the vagaries of these proteins in membrane mimetic environments and by the difficulties in handling them with conventional techniques. Designing and creating water-soluble analogues with preserved native structures offer an attractive alternative. We report here solution NMR studies of WSK3, a water-soluble analogue of the potassium channel KcsA. The WSK3 NMR structure (PDB ID code 2K1E) resembles the KcsA crystal structures, validating the approach. By more stringent comparison criteria, however, the introduction of several charged residues aimed at improving water solubility seems to have led to the possible formations of a few salt bridges and hydrogen bonds not present in the native structure, resulting in slight differences in the structure of WSK3 relative to KcsA. NMR dynamics measurements show that WSK3 is highly flexible in the absence of a lipid environment. Reduced spectral density mapping and model-free analyses reveal dynamic characteristics consistent with an isotropically tumbling tetramer experiencing slow (nanosecond) motions with unusually low local ordering. An altered hydrogen-bond network near the selectivity filter and the pore helix, and the intrinsically dynamic nature of the selectivity filter, support the notion that this region is crucial for slow inactivation. Our results have implications not only for the design of water-soluble analogues of membrane proteins but also for our understanding of the basic determinants of intrinsic protein structure and dynamics.
    Proceedings of the National Academy of Sciences 11/2008; 105(43):16537-42. · 9.74 Impact Factor
  • Anna Carnini, J D Lear, R G Eckenhoff
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    ABSTRACT: Anesthesia and surgery have been reported to produce long-term cognitive problems, and to accelerate neurodegenerative disorders in the elderly. In previous work, we found that inhaled anesthetics enhance fibril formation and cytotoxicity of amyloid beta peptide. In this work we show that the inhaled anesthetics halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) and isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) also favor intermediate oligomers of amyloid beta(1-40), and reduce solubility of amyloid beta(1-40) monomer. Size-exclusion chromatography, analytical ultracentrifugation and photo-induced cross-linking experiments indicate halothane enhancement of oligomeric species having molecular weight approximately 44-100 kDa. Bis-ANS fluorescence experiments revealed that halothane stabilizes a population of diffusible oligomers relative to the monomer or the mature fibril. These data show that inhaled anesthetics lower the amyloid beta(1-40) concentration necessary to initiate oligomer formation, probably by preferential binding to intermediate oligomers en route to fibril formation.
    Current Alzheimer Research 08/2007; 4(3):233-41. · 3.68 Impact Factor
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    ABSTRACT: The prevalence of the neurodegenerative disorders is increasing as life expectancy lengthens, and there exists concern that environmental influences may contribute to this increase. These disorders are varied in their clinical presentation, but appear to have a common biophysical initiation. At this level, it is both plausible and now proven that anesthetics can enhance aggregation of some disease-causing proteins. Although data in support of an interaction in animal models are still lacking, data from clinical studies indicate an association, which provides further cause for concern. Many opportunities exist for rapid progress at all levels on defining whether anesthetics do indeed contribute to the pathogenesis of these progressive, debilitating disorders.
    Anesthesiology Clinics 07/2006; 24(2):381-405.
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    ABSTRACT: The majority of surgical patients receive inhaled anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. The authors hypothesize that inhaled anesthetics contribute to these effects through a durable enhancement of peptide oligomerization. Light scattering, filtration assays, electron microscopy, fluorescence spectroscopy and size-exclusion chromatography was used to characterize the concentration-dependent effects of halothane, isoflurane, propofol, and ethanol on amyloid beta peptide oligomerization. Pheochromocytoma cells were used to characterize cytotoxicity of amyloid oligomers with and without the above anesthetics. Halothane and isoflurane enhanced amyloid beta oligomerization rates and pheochromocytoma cytotoxicity in vitro through a preference for binding small oligomeric species. Ethanol and propofol inhibited oligomerization at low concentration but enhanced modestly at very high concentration. Neither ethanol nor propofol enhanced amyloid beta toxicity in pheochromocytoma cells. Inhaled anesthetics enhance oligomerization and cytotoxicity of Alzheimer disease-associated peptides. In addition to the possibility of a general mechanism for anesthetic neurotoxicity, these results call for further evaluation of the interaction between neurodegenerative disorders, dementia, and inhalational anesthesia.
    Anesthesiology 10/2004; 101(3):703-9. · 5.16 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Background: The majority of surgical patients receive inhaled anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. The authors hypothesize that inhaled anesthetics contribute to these effects through a durable enhancement of peptide oligomerization.
    Anesthesiology 08/2004; 101(3):703-709. · 5.16 Impact Factor
  • Anesthesiology 01/2004; 101(3):703-709. · 5.16 Impact Factor

Publication Stats

172 Citations
239 Views
28.90 Total Impact Points

Institutions

  • 2008
    • Hospital of the University of Pennsylvania
      • Department of Anesthesiology and Critical Care
      Philadelphia, Pennsylvania, United States
  • 2007
    • National Research Council Canada
      Ottawa, Ontario, Canada
  • 2004
    • University of Pennsylvania
      • Department of Anesthesiology and Critical Care
      Philadelphia, PA, United States