EXPRESSION AND REGULATION OF BRAIN METALLOTHIONEIN

Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminal s and release it by a calcium-dependent mechanism. These ''vesicular'' pools of zinc are viewed as endogenous modulators of ligand- and volt age-gated ion channels. Metallothioneins (MTs) are low molecular weigh t zinc-binding proteins consisting of 25-30% cysteine, with no aromati c amino acids or disulfide bonds. The areas of the brain containing hi gh contents of zinc such as the retina, the pineal gland, and the hipp ocampus synthesize unique isoforms of MT on a continuous basis. The fo ur MT isoforms are thought to provide the neurons and glial elements w ith mechanisms to distribute, donate, and sequester zinc at presynapti c terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT . A similar nucleotide and amino acid sequence has made it difficult t o obtain cDNA probes and antibodies capable of distinguishing indisput ably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an addition al seven amino acids, is expressed mostly in the brain and to a very m inute extent in the intestine and pancreas; whereas MT-IV isoform is f ound in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic ve sicles, the regulation of the expression of MT isoforms is extremely i mportant in terms of maintaining the steady-state level of zinc and co ntrolling redox potentials. The concentration of zinc has been shown t o be altered in an extensive number of disorders of the central nervou s system, including alcoholism Alzheimer-type dementia, amyotrophic la teral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guill aine-Barre syndrome, hepatic encephalopathy, multiple sclerosis, Parki nson's disease, Pick's disease, retinitis pigmentosa, retinal dystroph y, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT is oforms and other low molecular weight zinc-binding proteins in these c onditions, diseases, disorders, or syndromes is being delineated at th is time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytoki ne-induced induction of MT provides a long-lasting protection to avert oxidative damage.