Neurology & Neurophysiology

Biography

Biography: Ludmila Zylinska

Abstract

Oscillations of cytosolic Ca²⁺ are necessary for cellular signaling and propagation of Ca²⁺ signal is an absolute requirement for the functioning of neuronal cells. Ca²⁺ appears to be a universal and ubiquitous signaling molecule, thereby in resting neuronal cells its concentration is kept at ~100 nM against 1-2 mM outside the cell. Inability to maintain calcium homeostasis in neurons underlies many neuropathologies. Ca²⁺ may elicit a variety of different responses based on the type of targeted neurotransmission pathways, and it regulates synaptic plasticity, controls neuronal growth and neuronal survival. The plasma membrane contains a high affinity Ca²⁺-ATPase (PMCA) that translocates Ca²⁺ from the cytosol to the extracellular environment. The enzyme is coded by four separate genes (PMCA1-4), among which PMCA₂ and PMCA₃ are considered as neuron-specific forms. In the brain, PMCA function declines progressively during aging, thus impaired calcium homeostasis may contribute to neurodegeneration. We have developed the stable transfected differentiated PC₁₂ cells with reduced level of PMCA₂ or PMCA₃, and the most critical finding was permanently increased resting Ca²⁺ concentration. Altered PMCA composition affected the expression level of several Ca²⁺-associated proteins (SERCA, calmodulin, calcineurin, neuromodulin) and certain types of voltage-gated calcium channels. We have also evidenced a novel PMCA role in regulation of bioenergetic pathways and mitochondrial activity. Interestingly, some changes could occur as adaptive processes protecting cells against calcium overload. Since age-related PMCA decrease has been documented, our modified PC₁₂ cells may be a useful model to clarify the biological changes in neurons as well as to study the vulnerability of cells to neurodegenerative insults.