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.
Highlights
Glucagon-like-peptide-1 (GLP-1) is a metabolic hormone secreted by intestinal endocrine L-cells and stimulates insulin secretion in a glucose-dependent manner [1]
All these data suggest that ganglion cells (GCs) express functional GABAA and GABAB receptors, but not GABAc receptors, and this is consistent with the results of in situ hybridization and immunohistochemistry showing that GCs express GABAA and GABAB receptors [23–27]
The endogenous Glucagon-like peptide-1 (GLP-1) is highly sensitive to degradation by dipeptidyl peptidase IV (DPP-IV) [28–32]; for this reason, we investigated the effects of the protease-resistant long-acting GLP-1 receptor (GLP-1R) agonist exendin-4 [28, 33, 34] on the GABA currents of GCs (Fig. 2A)
Summary
Glucagon-like-peptide-1 (GLP-1) is a metabolic hormone secreted by intestinal endocrine L-cells and stimulates insulin secretion in a glucose-dependent manner [1]. GLP1 is produced in the brain, from preproglucagon neurons, which are distributed in the solitary tract of the brain stem, and it functions as a neuropeptide [2–5]. This peptide has been implicated in modulating neuronal cell differentiation, neurite outgrowth, and performing neuroprotective functions through the activation of GLP-1 receptors (GLP-1Rs), class B sub-group G proteincoupled receptors [2, 6]. GLP-1 expression has been found in the vertebrate retina [7–9]. GLP-1R immunoreactivity has been observed in the ganglion cell layer (GCL) in the human and rat retina [7, 10–12], and sparse staining has been detected in the inner and outer nuclear layers of the human retina. Whether GLP-1 modulates retinal information processing is still largely unknown
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