Résumé :
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Hyperekplexia is a genetic neurological human disease, which is accompanied by muscular hypertonia, hyperreflexia, and hypokinesia. Hyperekplexia originates from a dysfunction of glycine receptor (GlyR) channels, which mediate fast inhibitory synaptic transmission in spinal cord, brainstem, retina and other areas of the nervous system of vertebrates. Several point mutations of the GlyR gene result in decreased activation of GlyR channels, leading to a reduction of inhibitory drive through glycinergic synapses and, consequently, to the development of motor disorders. Previously our team discovered a new mechanism for GlyR modulation: potentiation by intracellular calcium (Ca2+) involving a Ca2+-binding protein (Fucile et al., 2000). This mechanism could be exploited to increase activity of GlyR channels in glycinergic synapses in normal and pathological conditions. Here we analyzed the mechanisms of Ca2+-induced potentiation in neurons and in heterologous systems. We find out that neuronal Ca2+-binding protein (NECAB) is involved in Ca2+-dependent regulation of GlyRs. Overexpression of NECAB caused: (i) a decrease the apparent affinity to glycine and shift to the right of “dose-response” curve of glycine-induced currents in CHO, HEK-293 cells and in spinal neurons; (ii) a shortening of the decay time of glycinergic currents in spinal neurons. These observations suggest that the development of peptides mimicking the GlyR sequence responsible for binding with NECAB might be important for modulation inhibitory drive through glycinergic synapses. Such peptides, interacting with NECAB, should prevent its binding to the GlyR, thus leading to a functional up-regulation of GlyR channels. Such an approach is a promising avenue to develop pharmacological compounds upregulating GlyRs function in hyperekplexia models. Fucile S., De Saint Jan D., de Carvalho L.P., Bregestovski P., 2000. Fast potentiation of glycine receptor channels by intracellular calcium in neurons and transfected cells. Neuron 28: 571-583. ACKNOWLEDGEMENTS This work was supported by French Association against Myopathies (AFM) for M.Mukhtarov.
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