engleski

Uroguanylin increases Ca2+ concentration in astrocytes via guanylate cyclase C independent signaling pathway

INTRODUCTION: Guanylin peptides (GP), guanylin and uroguanylin (UGN), are intestinal peptides which activate guanylate cyclase C (GC-C) and increase cGMP concentration. GC-C is present not only in the intestine, but also in the Substantia nigra and Ventral tegmental areas of the brain where GP neuromodulate neuron activity. GC-C KO mice are the new animal model for ADHD. GC-C has also been reported in the hypothalamus where it plays an important role in the regulation of feeding and satiation. AIMS: The existence of cGMP/GC-C independent signaling pathway was suggested two decades ago ; however, the exact nature of the signaling pathway was never discovered. Therefore the aim of this study is to investigate the cGMP/GC-C independent signaling pathway in astrocytes which are a suitable model because they do not express GC-C. METHODS: In this study we performed patch clamp experiments and measured intracellular Ca2+ concentrations and pH in primary cultures of astrocytes and brain slices of wild type and GC-C KO mice. RESULTS: This study shows that GP hyperpolarized astrocyte membranes, which is opposite to depolarization caused by cGMP. By measuring intracellular concentration of Ca2+ we showed, for the first time, that UGN induces changes in intracellular Ca2+ levels in primary astrocyte cultures and in different regions of the brain, such as the hypothalamus, cerebral and cerebellar cortex. Furthermore, regulation of pH by astrocytes is important for neuronal function. GP regulate pH by changing transport of hydrogen and bicarbonate in astrocytes. CONCLUTION: The results of this study suggest that the effects of UGN on astrocytes via a Ca2+- dependent signaling pathway could be involved in modulation of neuronal activity. Grants: European Regional Development Fund, Operational Programme Competitiveness and Cohesion (K.K.01.1.1.01.0007). „Young researchers' career development project – training of doctoral students“ of the Croatian Science Foundation funded by the European Union from the European Social Fund.

patch-clamp ; pH ; GC-C KO mice ; guanylin peptides ; cGMP

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