BDNF regulates neuronal survival, differentiation, and synaptic plasticity. It affects the release of excitatory neurotransmitters and has been found to affect cardiovascular development and function.¹ Like many other neurotrophins, BDNF is a cleavage product of the BDNF precursor, proBDNF. This precursor may be cleaved by various proteases, intracellularly by furin and extracellularly by several proteases including prohormone convertases, plasminogen activator, MMP-3 and MMP-7 in vitro.^2,3

Two different trans-membrane receptor proteins mediate BDNF and proBDNF signal transduction: the TrkB, and the pan-neurotrophic receptor p75^NTR.⁴ ProBDNF has been demonstrated to induce TrkB phosphorylation in vitro and to bind p75^NTR and sortilin to promote apoptosis.^5,6

In many cases, the full prodomain region derived from the protein precursor has biological functions, for instance; the prodomain of the transforming growth factor β (TGFβ) affects the dimerization and folding as well as the activity of the mature proteins via non-covalent association. The propeptide of the bone morphogenetic proteins BMP-4 and BMP-7 regulates the diffusion and distribution of these growth factors within the extracellular matrix.^7,8 The prodomain region of the BDNF precursor plays an important role in regulating its intracellular trafficking to secretory pathways.⁹ However, the role of the full BDNF-prodomain, which is a product of proteolytic cleavage of proBDNF, is not clearly understood. Furthermore, binding competition studies suggest that binding sites for BDNF prodomain are located in the tunnel of the ten-bladed b-propeller domain of sortilin.¹⁰