Table of Contents

April 2004; 4 (2)

Speaking of Pharmacology

    • Peter C. Preusch

    Integrative and Organ Systems Pharmacology: A New Initiative from the National Institute of General Medical Sciences

    Mol Interv April 2004 4:72-73; doi:10.1124/mi.4.2.1

Crosstalk

  • Robert F. Furchgott: A Pharmacologist’s Pharmacologist

    Mol Interv April 2004 4:74-78; doi:10.1124/mi.4.2.2

Viewpoints

    • Christopher D. Heger and
    • Ruth N. Collins

    Platelet Activation and “Crossover Appeal”: Rab and Rho Families United by Common Links to Serotonin

    Mol Interv April 2004 4:79-81; doi:10.1124/mi.4.2.3

    Tryptophan hydroxylase 1 (Tph1) is essential for the production of serotonin. Tph1−/− mice have increased risk of thromboembolism, although there appears to be no observable change to the ultrastructure of the platelets in the knockout mice. The platelets are deficient in their ability to adhere to wounded surfaces and this arises from a decrement in secreted adhesive granular proteins. Surprisingly, the defective function of the platelets can be traced back to an impairment in the transamidation of Rab4 and RhoA by serotonin. During the normal process of platelet activation and granular protein secretion, these GTPases are activated; however, in the knockout mice, lack of serotonin translates into lack of platelet activation and adhesion, leading to increased likelihood of thrombosis.

    • Panagiotis A. Tsonis

    Stem Cells from Differentiated Cells

    Mol Interv April 2004 4:81-83; doi:10.1124/mi.4.2.4

    A recent study by Chen et al. characterizes the small molecule reversine, a substituted purine analog, as a signal for the dedifferentiation of myotubes (formed from a myoblastic cell line) back into progenitor cells that can then differentiate, under appropriate conditions, into osteoblasts or adipocytes. The authors speculate that the process may involve protein kinases and that further work will identify the spe-cific kinase or other molecules to which reversine binds. This work is of extraordinary interest and may have landmark importance to regeneration research (i.e., reforming nerves, limbs, and organs) and clinical medicine.

    • Sungwoo Kim,
    • Gus R. Rosania,
    • and Young-Tae Chang

    Dedifferentiation? What’s next?

    Mol Interv April 2004 4:83-85; doi:10.1124/mi.4.2.5

    Not so fast! Several things need to be considered before we conclude that Chen et al. have a dedifferentiating agent on their hands. The verification of small molecules as tissue- or cell-type dedifferentiating agents will require greatly sophisticated techniques and the identification of the direct molecular targets of said small molecules. By knowing what pitfalls to avoid, intelligent small-molecule design and testing may proceed more expediently.

Reviews

    • Pavlina T. Ivanova,
    • Stephen B. Milne,
    • Jeffrey S. Forrester,
    • and H. Alex Brown

    LIPID Arrays: New Tools in the Understanding of Membrane Dynamics and Lipid Signaling

    Mol Interv April 2004 4:86-96; doi:10.1124/mi.4.2.6

    Once regarded as little more than a tiny bag whose sole purpose was to retain the really interesting constituents of the cell, the plasma membrane is now appreciated for its vital elegance. Cell surface receptors in particular have become a staple of biomedical research, and the turnover of membrane phospholipid is a fundamental concept in signal-transducing mechanisms. Still, the dynamic complexity of lipid signaling has gone largely unexplored, primarily due to difficulties in identifying the multiple lipid species that fall under each of a slew of rubrics, such as “phosphoinositide,” “phosphatidylcholine,” and “diacylglycerol.” Today, advancing technologies in mass spectrometry and computational analysis promise to deliver detailed snapshots of the full complement of lipid species over the course of cellular responses to physiological cues.

    • Natalie J. Serkova,
    • Uwe Christians,
    • and Leslie Z. Benet

    Biochemical Mechanisms of Cyclosporine Neurotoxicity

    Mol Interv April 2004 4:97-107; doi:10.1124/mi.4.2.7

    Of the several immunosuppressive drugs used to facilitate organ transplantation, the undecapeptide cyclosporine serves as a cornerstone in the prevention of graft rejection. A high percentage of treated patients, however, suffer from serious neurotoxic side effects. Paradoxically, cyclosporine ameliorates brain injury induced by cerebral ischemia–reperfusion in vivo, and this neuroprotective function has magnified interest in elucidating the biochemical mechanisms of cyclosporine action in the central nervous system. Magnetic resonance spectroscopy (MRS) is being increasingly used to quantify metabolic consequences of drug neurotoxicity and has revealed that cyclosporine evokes morphological changes in the brain.

    • Dennis L. Murphy,
    • Alicja Lerner,
    • Gary Rudnick,
    • and Klaus-Peter Lesch

    Serotonin Transporter: Gene, Genetic Disorders, and Pharmacogenetics

    Mol Interv April 2004 4:109-123; doi:10.1124/mi.4.2.8

    The serotonin transporter (SERT) modulates the concentration of serotonin in extracellular fluids. Given this essential role, genetic variability in SERT is of considerable interest in elucidating disorders of serotoninergic activity. Genetic disturbances within the chromosome 17q region where SERT is located have been mapped and may be associated with a variety of disorders, including autism, attention deficit-hyperactivity disorder, bipolar disorder, and Tourette’s syndrome. Studies of knockout mice, moreover, suggest SERT as a determinant of additional clinical conditions, ranging from irritable bowel syndrome to obesity. The association of certain polymorphisms with poorer therapeutic responses to SERT antagonists, including more frequent serious side effects, also has important implications for the treatment of emotional disorders.

Beyond the Bench

Net Results

Outliers

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This Issue

April 2004; 4 (2)
Cover
  1. Speaking of Pharmacology
  2. Crosstalk
  3. Viewpoints
  4. Reviews
  5. Beyond the Bench
  6. Net Results
  7. Outliers

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