Journal
NEUROSCIENCE BULLETIN
Volume 38, Issue 6, Pages 622-636Publisher
SPRINGER
DOI: 10.1007/s12264-022-00826-9
Keywords
Glucagon-like peptide-1; Exendin-4; GABA current; Retinal ganglion cells; Neuromodulation
Categories
Funding
- National Natural Science Foundation of China [81790640, 32070989, 31872766, 31571075, 82070993, 31571072]
- Ministry of Science and Technology of China [2011CB504602, 2015AA020512]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX01, SZSM202011015]
- ZJLab
- Shanghai Center for Brain Science and Brain-Inspired Technology
- Sanming Project of Medicine in Shenzhen [SZSM202011015]
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This study investigates the role of glucagon-like peptide-1 (GLP-1) in the retina. The researchers demonstrate that GLP-1 or its receptor GLP-1R can suppress GABAR-mediated currents in retinal ganglion cells through a specific signaling pathway involving cAMP-PKA/IP3/Ca2+/CaM/CaMKII. This finding indicates a previously unknown mechanism of GLP-1 action in the retina.
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 gamma-aminobutyric acid receptor (GABAR)-mediated currents through GLP-1Rs in isolated rat retinal ganglion cells (GCs). Pre-incubation with the stimulatory G protein (G(s)) 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 Rp-cAMP/KT-5720. The exendin-4 effect was accompanied by an increase in [Ca2+](i) of GCs through the IP3-sensitive pathway and was blocked in Ca2+-free solution. Furthermore, when the activity of calmodulin (CaM) and CaM-dependent 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(s)/cAMP-PKA/IP3/Ca2+/CaM/CaMKII signaling pathway, following the activation of GLP-1Rs.
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