Uroguanylin Increases Ca2+ Concentration in Astrocytes via Guanylate Cyclase C-independent Signalling Pathway

Abstract Background: Guanylin peptides (GPs), guanylin and uroguanylin (UGN), are intestinal peptides which activate guanylate cyclase C (GC-C) and increase cGMP concentration. In the brain, GC-C is located in the midbrain where GPs neuromodulate neuron activity. GC-C has also been reported in the hypothalamus where it plays an important role in the regulation of feeding and satiety. The existence of cGMP/GC-C independent signalling pathway for GPs was suggested two decades ago; however, the exact nature of the signalling pathway has not been discovered. Therefore, the aim of this study is to investigate the cGMP/GC-C independent signalling pathway in astrocytes which are a suitable model because they do not express GC-C. Results: In this study, we performed patch clamp and intracellular Ca2+ concentrations and pH measurements in primary cultures of astrocytes and brain slices of WT, UGN KO, and GC-C KO mice. The function of GC-C independent signalling pathway in cerebellum was determined by behaviour tests in UGN and GC-C KO mice. We showed, for the first time, that UGN induces changes in intracellular Ca2+ levels in different mouse brain regions. In addition to midbrain and hypothalamus, GC-C is also expressed in cerebral and cerebellar cortex. Presence of two signalling pathways in the cerebellum (UGN hyperpolarized Purkinje cells via GC-C and increased intracellular Ca2+ concentration in astrocytes) lead to a difference in motoric function in GC-C KO and UGN KO mice probably via difference in regulation of intracellular pH in astrocytes. Conclusion: The results of this study suggest that the effects of UGN on astrocytes via a Ca2+- dependent signalling pathway could be involved in the modulation of neuronal activity.