Signaling Mechanism for Modulation by GLP-1 and Exendin-4 of GABA Receptors on Rat Retinal Ganglion Cells

Glucagon-like peptide-1(GLP-1)is expressed in retinal neurons,but its role in the retina is largely unknown.Here,we demonstrated that GLP-1 or the GLP-1 receptor(GLP-1R;a G protein-coupled receptor)agonist exendin-4 suppressed-aminobutyric acid receptor(GABAR)-mediated currents through GLP-1Rs in isolated rat retinal ganglion cells(GCs).Pre-incubation with the stimulatory G protein(G,)inhibitor NF 449 abolished the exendin-4 effect.The exendin-4-induced suppression was mimicked by perfusion with 8-Br-cAMP(a cAMP analog),but was eliminated by the protein kinase A(PKA)inhibitor RpcAMP/KT-5720.The_exendin-4 effect was accompanied by an increase in[Ca2+];of GCs through the IP3-sensitive pathway and was blocked in Ca2+-free solution.Furthermore,when the activity of calmodulin(CaM)and CaMdependent protein kinase II(CaMKII)was inhibited,the exendin-4 effect was eliminated.Consistent with this,exendin-4 suppressed GABAR-mediated light-evoked inhibitory postsynaptic currents in GCs in rat retinal slices.These results suggest that exendin-4-induced suppression may be mediated by a distinct G,/cAMP-PKA/IPs/Ca+/CaM/CaMKIl signaling pathway,following the activation of GLP-1Rs.