Table of Contents

April 2005; 5 (2)

Reflections

    • Stanley Scheindlin

    the Duplicitous Nature of Inorganic Arsenic

    Mol Interv April 2005 5:60-64; doi:10.1124/mi.5.2.1

Crosstalk

Viewpoints

    • Luigia Santella

    NAADP: A New Second Messenger Comes of Age

    Mol Interv April 2005 5:70-72; doi:10.1124/mi.5.2.3

    Nicotinic acid adenine dinucleotide phosphate (NAADP) is one of the most potent stimulators of intracellular Ca2+ mobilization in a variety of cell types. Its role in physiological processes is increasingly demonstrated by NAADP increases following cellular stimulation. As a second messenger NAADP shows unique features such as the ability to mobilize Ca2+ from stores that are physically distinct from those connected to the Ca2+ channels located in the endoplasmic reticulum, namely, the inositol-1,4,5-trisphosphate and the cyclic-ADP-ribose/ ryanodine receptors. Furthermore, the NAADP-induced self-inactivation mechanism is suggestive of an irreversible binding of NAADP to its putative receptor.

    • Antony Galione and
    • Ole H. Petersen

    The NAADP Receptor: New Receptors or New Regulation?

    Mol Interv April 2005 5:73-79; doi:10.1124/mi.5.2.4

    Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent calcium mobilizing messenger yet discovered. Its action has now been reported in a large number of cell types from a diverse array of organisms, and in some cases linked to the transduction of specific cellular stimuli. However, what is controversial is the nature of its target calcium release channel, as well as the subcellular localization of its receptor. Some have proposed that NAADP activates a novel calcium release channel distinct from the two major classes of channels known, the inositol trisphosphate receptors and ryanodine receptors. However, others have suggested that it acts in a novel way to regulate a known calcium release channel, the ryanodine receptor.

    • Leslie Z. Benet

    There Are No Useful CYP3A Probes that Quantitatively Predict the In Vivo Kinetics of Other CYP3A Substrates and No Expectation that One Will Be Found

    Mol Interv April 2005 5:79-83; doi:10.1124/mi.5.2.5

    The search for a substrate that may serve as a probe to quantitatively predict the in vivo kinetics of cytochrome P450 3A (CYP3A) drugs has been of particular interest because more than half of all human drugs appear to be substrates for this enzyme. Even three closely related 1,4-benzodiazepines-alprazolam, midazolam, and triazolam-are inadequate probes to predict the pharmacokinetics of each other in an individual. If these drugs--all metabolized through the same CYP3A pathways in humans, all FDA Biopharmaceutical Classification System Class 1 compounds exhibiting high solubility and high permeability and thus unaffected by transporter differences--cannot quantitatively predict the pharmacokinetics of their closely related congeners, there is little hope that any quantitative CYP3A probe will ever be found.

Reviews

    • Terrance D. Barrett,
    • David J. Triggle,
    • Michael J.A. Walker,
    • and Donald H. Maurice

    Mechanism of Tissue-Selective Drug Action in the Cardiovascular System

    Mol Interv April 2005 5:84-93; doi:10.1124/mi.5.2.6

    The premise of rational drug design is that detailed structural knowledge of a targeted macromolecule can guide the synthesis of small-molecule drugs—a premise that is sometimes undermined by physiological realities that preclude target “drugability.” Some pharmacologists, on the other hand, are moving towards the rational exploitation of physiological and pathophysiological conditions per se, in order to achieve therapeutic success with small-molecule drugs. In the cardiovascular system, for example, ionic properties arising from myocardial ischemia may provide the precise conditions in which channel blockers can prevent ventricular fibrillation, and the signaling milieu created by innervation of the human penile vasculature may be key to drugs that selectively ameliorate erectile dysfunction.

    • Marc W. Fariss,
    • Catherine B. Chan,
    • Manisha Patel,
    • Bennett Van Houten,
    • and Sten Orrenius

    ROLE of MITOCHONDRIA in TOXIC OXIDATIVE STRESS

    Mol Interv April 2005 5:94-111; doi:10.1124/mi.5.2.7

    Considerable experimental and clinical evidence supports the importance of mitochondria and mitochondrial oxidative damage as a critical target and event, respectively, responsible for toxic oxidative stress and numerous common diseases. This is supported, in part, by the demonstration of the dramatic protection of cells against toxic oxidative stress following the enrichment of mitochondrial membranes with vitamin E. Several oxidative events implicated in toxic oxidative stress include alterations in mitochondrial lipids (e.g., cardiolipin), mitochondrial DNA, and mitochondrial proteins (e.g., aconitase and uncoupling protein 2). Compelling information is provided to support the importance of these four different mitochondrial targets in toxic oxidative stress and related diseases.

    • Harm J. Knot,
    • Ismail Laher,
    • Eric A. Sobie,
    • Silvia Guatimosim,
    • Leticia Gomez-Viquez,
    • Hali Hartmann,
    • Long-Sheng Song,
    • W.J. Lederer,
    • Wolfgang F. Graier,
    • Roland Malli,
    • Maud Frieden,
    • and Ole H. Petersen

    Twenty Years of Calcium Imaging: Cell Physiology to Dye For

    Mol Interv April 2005 5:112-127; doi:10.1124/mi.5.2.8

    With the use of fluorescent imaging over the past two decades, Ca2+ has proven to be an unexpectedly versatile signaling molecule. Ca2+ concentrations within numerous spatial domains are finely modulated to generate selective signals in a variety of cellular contexts, and the timed regulation of Ca2+ concentration adds another dimension to signaling. Ca2+ transients, sparks, waves, and oscillations describe signaling at the global/cellular as well as subsellular levels; these terms not only bespeak the biological elegance of signaling processes, but also reflect the creativity of the biologists who find ways to explore the versatility of Ca2+ signaling.

Beyond the Bench

Net Results

  • Sites of interest on the World Wide Web—edited by Rick Neubig and David Roman

    Mol Interv April 2005 5:130

Outliers

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This Issue

April 2005; 5 (2)
Cover
  1. Reflections
  2. Crosstalk
  3. Viewpoints
  4. Reviews
  5. Beyond the Bench
  6. Net Results
  7. Outliers

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