ABSTRACT
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 γ-aminobutyric acid receptor (GABAR)-mediated currents through GLP-1Rs in isolated rat retinal ganglion cells (GCs). Pre-incubation with the stimulatory G protein (Gs) 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 Gs/cAMP-PKA/IP3/Ca2+/CaM/CaMKII signaling pathway, following the activation of GLP-1Rs.
ABSTRACT
Due to the advantages in genetic manipulation, mice have become one of the most commonly used mammalian models for the study of mechanisms underlying myopia development. However, the vast majority of laboratory mouse strains are incapable of synthesizing melatonin, a neurohormone that may play an important role in myopia generation in humans. The present study investigated refractive development profiles in the CBA/CaJ mouse, a strain proficient in melatonin, and determined whether and how its refractive development could be affected by form-deprivation. Eccentric infrared photoretinoscopy revealed that this animal could be stably refracted, and the refractive error underwent developmental changes, which increased with age in the hyperopic direction and eventually got stable approximately 9 weeks after birth. The absolute values of refractive error in CBA/CaJ mice were larger than those of age-matched C57BL/6 mice, whereas the time points when refractive error reached steady state were similar between the two strains. Five weeks of form-deprivation applied to 3-week-old CBA/CaJ mice by translucent occluder wear caused a significant myopic shift in refractive error, indicating that this strain could be adequately used as a myopia model.