Abstract
STKE Behavioral sensitization to cocaine, which occurs following repeated administration, involves long-lasting changes in glutamatergic transmission in the nucleus accumbens. Cocaine elicits changes in the expression of genes encoding Homer scaffolding proteins [which exist in complexes with metabotropic glutamate receptors (mGluRs)], and Szumlinski et al . have now investigated the effects of Homer deletion. Mice lacking Homer1 or Homer2 showed enhanced sensitivity to cocaine-induced place conditioning (preference for environments associated with cocaine administration), as well as an enhanced locomotor response to cocaine. Furthermore, these mice had decreased basal extracellular glutamate concentration in the nucleus accumbens compared to wild-type mice (as occurs with repeated cocaine administration) and, like rats in withdrawal from repeated cocaine administration, showed increased extracellular glutamate following cocaine exposure. Restoring Homer2 reversed the effects on conditioning and on the behavioral and neurochemical response to cocaine. Homer2 knockout also led to more rapid development of cocaine self-administration and, as in cocaine-sensitized animals, attenuated the increase in extracellular glutamate produced by a mGluR1 agonist. Thus, lack of Homer2 mimics many aspects of the sensitization seen with withdrawal from repeated cocaine administration, leading the authors to propose that Homer proteins may play a key role in cocaine addiction. — EMA Neuron 43 , 401 (2004).
Highlights
A recent theme in explanations of the catalytic efficacy of protein enzymes is the harnessing of correlated fluctuations of the polypeptide backbone and amino acid side chains
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Summary
A recent theme in explanations of the catalytic efficacy of protein enzymes is the harnessing of correlated fluctuations (at the atomic scale) of the polypeptide backbone and amino acid side chains. In some cases, these motions would serve to align and reposition chemically powerful groups within the active site, whereas in other cases, they would act to control the entry of reactants and exit of products. Using CO as an inactive analog of O2, they find that adding a three-carbon unit (by swapping valine for glycine) obstructs access, implying that fluctuations, at least in this portion of the enzyme, are constrained to the extent that a diatomic gas cannot squeeze through. Replacing glycine (blue) with valine (green) closes the O2 channel (orange)
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