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

To investigate the cyclic guanosine monophosphate (cGMP)/guanylate cyclase C (GC-C)-independent signaling pathway in astrocytes, which are a suitable model due to their lack of GC-C expression. Patch clamp was performed and intracellular Ca2+ concentrations and pH were measured in primary astrocyte cultures and brain slices of wild type (WT) and GC-C knockout (KO) mice. The function of GC-C-independent signaling pathway in the cerebellum was determined by behavior tests in uroguanylin (UGN) KO and GC-C KO mice. We showed for the first time that UGN changed intracellular Ca2+ levels in different brain regions of the mouse. In addition to the midbrain and hypothalamus, GC-C was expressed in the cerebral and cerebellar cortex. The presence of two signaling pathways in the cerebellum (UGN hyperpolarized Purkinje cells via GC-C and increased intracellular Ca2+ concentration in astrocytes) led to a different motoric function in GC-C KO and UGN KO mice, probably via different regulation of intracellular pH in astrocytes. The UGN effects on astrocytes via a Ca2+-dependent signaling pathway could be involved in the modulation of neuronal activity.