Glucagon-Like Peptide-2 (GLP-2) Modulates the cGMP Signalling Pathway by Regulating the Expression of the Soluble Guanylyl Cyclase Receptor Subunits in Cultured Rat Astrocytes

Abstract

The aim of this work was to study the effect of glucagon-like peptide-2 (GLP-2) on the cyclic guanosine monophosphate (cGMP) signalling pathway and whether insulin or epidermal growth factor (EGF) might modulate the effects of GLP-2. GLP-2 produced a dose-dependent decrease in intracellular sodium nitroprusside-induced cGMP production. However, insulin induced an increase in the levels of cGMP that was dose-dependently decreased by the addition of GLP-2. By contrast, EGF induced a decrease in cGMP production, which was further reduced by the addition of GLP-2. To assess whether variations in cGMP production might be related with changes in some component of soluble guanylyl cyclase (sGC), the expression of the α1, α2, and β1 subunits were determined by Western blot analysis. At 1 h, GLP-2 produced a decrease in the expression of both α1 and β1 in the cytosolic fraction, but at 24 h only β1was reduced. As expected, insulin induced an increase in the expression of both subunits after 1 h of incubation; this was decreased by the addition of GLP-2. Likewise, incubation with EGF for 24 h produced a decrease in the expression of both subunits that was maximal when GLP-2 was added. In addition, incubation with insulin for 1 h produced an increase in the expression of the α2 subunit, which was reduced by the addition of GLP-2. These results suggest that GLP-2 inhibits cGMP production by decreasing the cellular content of at least one subunit of the heterodimeric active form of the sGC, independently of the presence of insulin or EFG. This may open new insights into the actions of this neuropeptide.

GLP-1 and GLP-2 Orchestrate Intestine Integrity, Gut Microbiota, and Immune System Crosstalk

“…GLP-2 has a half-life of 7 minutes during which it exerts its action through binding to GLP-2R [ 63 , 64 ]. Depending on the GLP-2R expressing tissues (gastrointestinal tract, CNS, mesenteric fat, lymph nodes, pancreas, liver, bladder, and spleen) [ 65 ], GLP-2 employs different signaling pathways to exerts its biological effects such as production of cyclic AMP [ 66 ], increase of intracellular calcium, inhibition of glycogen synthase kinase-3, and targeted gene expression [ 65 , 67 ] ( Figure 1 A). For instance, binding of GLP-2 to its receptor in the CNS inhibits food intake [ 68 , 69 ] and gastric emptying through the melanocortin receptor-4 (MC4R) signaling pathway [ 70 ].…”