TrkB and the calpain dependent-Tc TrkB receptor isoforms: possible neurological therapeutic targets

Abstract

Several neurological conditions share a characteristic feature: an increase in intracellular calcium levels ([Ca2+]i). It has been demonstrated that calcium influx induces changes ranging from an increase in the expression levels of several genes to the activation of proteases such as calpains. Calpains are a family of Ca2+-dependent non-lysosomal cysteine proteases, whose substrates include several proteins that play critical roles in several cellular functions including synaptic plasticity and neuronal apoptosis. TrkB is a type of tyrosine related kinase receptor that can promote neuronal survival and differentiation upon ligand binding. It has been recently shown that in several neurological diseases, the level of full-length TrkB protein decreases before the onset of neuronal death due to one of two different processes: a) a reverse regulation of TrkB isoforms mRNA, or b) calpainmediated processing of TrkB full-length, which yields a truncated form of TrkB (Tc-TrkB). Because the most notorious feature of calpain proteolytic activity is that the products of calpain-mediated leavage may have biological activity, here we review the hypotheses by which calpain- generated isoform Tc-TrkB may perform biological functions.