S100B Protein, A Damage-Associated Molecular Pattern Protein in the Brain and Heart, and Beyond

Abstract

S100B belongs to a multigenic family of Ca(2+)-binding proteins of the EF-hand type and is expressed in high abundance in the brain. S100B interacts with target proteins within cells thereby altering their functions once secreted/released with the multiligand receptor RAGE. As an intracellular regulator, S100B affects protein phosphorylation, energy metabolism, the dynamics of cytoskeleton constituents (and hence, of cell shape and migration), Ca(2+) homeostasis, and cell proliferation and differentiation. As an extracellular signal, at low, physiological concentrations, S100B protects neurons against apoptosis, stimulates neurite outgrowth and astrocyte proliferation, and negatively regulates astrocytic and microglial responses to neurotoxic agents, while at high doses S100B causes neuronal death and exhibits properties of a damage-associated molecular pattern protein. S100B also exerts effects outside the brain; as an intracellular regulator, S100B inhibits the postinfarction hypertrophic response in cardiomyocytes, while as an extracellular signal, (high) S100B causes cardiomyocyte death, activates endothelial cells, and stimulates vascular smooth muscle cell proliferation.

Figure 1

Schematic representation of extracellular effects of S100B in brain, heart, and vasculature. (a) At low concentrations, S100B promotes neuronal survival and stimulates neurite outgrowth via stimulation of RAGE signaling. (b) At high concentrations, S100B causes neuronal death both directly via excessive stimulation of RAGE signaling in neurons and indirectly via RAGE-dependent activation of microglia and astrocytes. (c) At high concentrations, S100B stimulates VSMC proliferation via RAGE activation. See text for details. (d) S100B released from necrotic cardiomyocytes kills nearby, surviving cardiomyocytes via RAGE activation.