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Thread: Scientists Find Key Pain Protein -- Study

  1. #1

    Scientists Find Key Pain Protein -- Study

    Thursday January 10 12:04 PM ET
    Scientists Find Key Pain Protein -- Study
    By Gene Emery

    BOSTON (Reuters) - Researchers have identified a key protein that controls severe pain, a discovery that might someday allow more relief for those who suffer intractable pain from terminal cancer, chronic backaches and other problems, according to Thursday's issue of the journal Cell.

    The protein is known by the acronym DREAM. In tests on mice bred to have a defective form of DREAM, the researchers discovered the animals seem completely normal, except their sensitivity to pain was greatly diminished.

    And while there are many types of pain, disabling the DREAM protein seems to reduce them all, said Dr. Josef Penninger of the University of Toronto, a coauthor of the study.

    Pain is vital to survival, allowing us to quickly draw away from scalding water or a sharp object. DREAM, according to the new research, keeps people sensitized to pain.

    But over time, such as after a person experiences a cut, the sharp pain fades because the DREAM protein becomes disabled, Penninger told Reuters in a telephone interview.

    ``DREAM lets you feel pain. When it doesn't work anymore, you don't feel it anymore.''

    If researchers could find a way to disable the protein, it could lead to a new and perhaps more effective method of pain control, he said.

    However, he cautioned that finding such a treatment could be challenging because the protein works deep inside individual cells, making it less accessible to drugs.

    ``This is simply a beginning,'' Penninger said. ``But if you can change DREAM, you can change pain.''

    The DREAM protein was discovered by other researchers but was originally implicated in Alzheimer's disease (news - web sites) and heart function. Thus, when the people in Penninger's laboratory created a strain of mice that lacked a properly working DREAM protein, they expected to see heart and memory problems.

    Instead, testers at NeuroDetective in Alberta, which screens mice strains for various defects, reported back to Penninger that the hearts and memory skills seemed fine. However, the animals weren't responding normally to pain.

    Mice with the defective DREAM protein appeared to feel about 50 percent less sharp pain when exposed to heat or some other stimulus.

    A treatment based on control of DREAM would be particularly useful to people with chronic pain conditions, Penninger said. For example, people with chronic back pain are often plagued because the more pain they experience, the worse the pain seems to become.

    ``The more they have, the more sensitive they get to it,'' he said. ``In DREAM mutants, there was no sensitization whatsoever. ... With every pain we tested them with, the pain was much, much reduced,'' he said.

    DREAM stands for downstream regulatory element antagonistic modulator.

  2. #2
    The paper reporting DREAM association with pain has not yet been put on the Medline database but here are earlier papers that describe the protein and what it does:


    • Carrion AM, Link WA, Ledo F, Mellstrom B and Naranjo JR (1999). DREAM is a Ca2+-regulated transcriptional repressor. Nature. 398 (6722): 80-4. Summary: Fluxes in amounts of intracellular calcium ions are important determinants of gene expression. So far, Ca2+-regulated kinases and phosphatases have been implicated in changing the phosphorylation status of key transcription factors and thereby modulating their function. In addition, direct effectors of Ca2+-induced gene expression have been suggested to exist in the nucleus, although no such effectors have been identified yet. Expression of the human prodynorphin gene, which is involved in memory acquisition and pain, is regulated through its downstream regulatory element (DRE) sequence, which acts as a location-dependent gene silencer. Here we isolate a new transcriptional repressor, DRE-antagonist modulator (DREAM), which specifically binds to the DRE. DREAM contains four Ca2+-binding domains of the EF-hand type. Upon stimulation by Ca2+, DREAM's ability to bind to the DRE and its repressor function are prevented. Mutation of the EF-hands abolishes the response of DREAM to Ca2+. In addition to the prodynorphin promoter, DREAM represses transcription from the early response gene c-fos. Thus, DREAM represents the first known Ca2+-binding protein to function as a DNA-binding transcriptional regulator. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=10078534> Instituto de Neurobiologia S. Ramon y Cajal, CSIC, Madrid, Spain.


    • Jo DG, Kim MJ, Choi YH, Kim IK, Song YH, Woo HN, Chung CW and Jung YK (2001). Pro-apoptotic function of calsenilin/DREAM/KChIP3. Faseb J. 15 (3): 589-91. Summary: Apoptotic cell death and increased production of amyloid b peptide (Ab) are pathological features of Alzheimer's disease (AD), although the exact contribution of apoptosis to the pathogenesis of the disease remains unclear. Here we describe a novel pro-apoptotic function of calsenilin/DREAM/KChIP3. By antisense oligonucleotide-induced inhibition of calsenilin/DREAM/KChIP3 synthesis, apoptosis induced by Fas, Ca2+-ionophore, or thapsigargin is attenuated. Conversely, calsenilin/DREAM/KChIP3 expression induced the morphological and biochemical features of apoptosis, including cell shrinkage, DNA laddering, and caspase activation. Calsenilin/DREAM/KChIP3-induced apoptosis was suppressed by caspase inhibitor Z-VAD and by Bcl-XL, and was potentiated by increasing cytosolic Ca2+, expression of Swedish amyloid precursor protein mutant (APPSW) or presenilin 2 (PS2), but not by a PS2 deletion lacking its C-terminus (PS2/411stop). In addition, calsenilin/DREAM/KChIP3 expression increased Ab42 production in cells expressing APPsw, which was potentiated by PS2, but not by PS2/411stop, which suggests a role for apoptosis-associated Ab42 production of calsenilin/DREAM/KChIP3. <http://www.fasebj.org/cgi/content/full/15/3/589
    http://www.ncbi.nlm.nih.gov/entrez/q...uids=11259376> Department of Life Science, Kwangju Institute of Science and Technology, Puk-gu, Kwangju 500-712, Korea.

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