Peptides modeled after the α-domain of metallothionein induce neurite outgrowth and promote survival of cerebellar granule neurons

Metallothionein (MT) is a metal-binding protein capable of preventing oxidative stress and apoptotic cell death in the central nervous system of mammals, and hence is of putative therapeutic value in the treatment of neurodegenerative disorders. Recently, we demonstrated that a peptide modeled after the β-domain of MT, EmtinB, induced neurite outgrowth and increased neuronal survival through binding to receptors of the low-density lipoprotein receptor family (LDLR). The present study identified two MT α-domain-derived peptide sequences termed EmtinAn and EmtinAc, each consisting of 14 amino acids, as potent stimulators of neuronal differentiation and survival of primary neurons. In addition, we show that a peptide derived from the N-terminus of the MT β-domain, EmtinBn, promotes neuronal survival. The neuritogenic and survival promoting effects of EmtinAc, similar to MT and EmtinB but not EmtinAn, were dependent on the functional integrity of LDLR. Moreover, EmtinAn and EmtinAc induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt). We suggest that multiple functional sites of MT serve to cross-link MT receptor(s), thereby transducing signals leading to an increase in neurite outgrowth and survival.