THE FUNCTIONAL-SIGNIFICANCE OF BRAIN METALLOTHIONEINS

Metallothioneins (MTs) are ubiquitous low molecular weight proteins ch aracterized by their abundant content of cysteines, Two MT isoforms, M T-I and MT-II, are expressed coordinately in all mammalian tissues, In the CNS, MT-I and MT-II are conspicuously absent from neuronal popula tions, yet abundant in fibrous and protoplasmic astrocytes. A newly id entified brain-specific MT gene, MT-III, is predominantly expressed in zinc-containing neurons of the hippocampus and absent from glial elem ents, MTs have been implicated as regulator molecules in gene expressi on, homeostatic control of cellular metabolism of metals, and cellular adaptation to stress. MTs store and release essential metals, such as zinc and copper, maintaining the low intracellular concentration of f ree essential metals. Thus, MTs fulfill a regulatory capacity and infl uence transcription, replication, protein synthesis, metabolism, as we ll as other zinc-dependent biological processes, Because MT-III is par ticularly abundant in zinc-containing neurons of the hippocampus, it i s likely to play an important role in neuromodulation by zinc-containi ng neurons and to act as a sink for free zinc, It may also play an eti ologic role in various pathophysiological conditions associated with i ncreased extracellular zinc, Studies demonstrating that MT-III prevent s neuronal sprouting in vitro, appears to be downregulated in Alzheime r's disease, and that MT-III ''knockout'' mice appear highly sensitive to kainate-induced seizures have focused growing attention on the eti ologic role of MT-III in neurodegeneration.