Gamma‐aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system (CNS). The biological effects of GABA are mediated by activating its receptors, GABA_A or GABA_B, which are distributed across various tissues, predominantly in the brain and retina. The retina is a neural tissue responsible for receiving and transducing light stimuli. Within this tissue, GABA receptors (GABARs) primarily mediate lateral inhibition in the retina. In recent years, several studies have focused on elucidating the potential role of GABARs in retinal diseases, such as diabetic retinopathy (DR), retinitis pigmentosa (RP), glaucoma, and age‐related macular degeneration (AMD). This review aims to present the most significant findings from recent years regarding the involvement of GABA receptors in retinal pathologies. Additionally, it highlights the potential of GABA receptors as targets for developing precise therapies or adjunctive strategies for treating retinal diseases.

GABA receptors are classically known for driving neuronal hyperpolarization and modulating synaptic transmission. In glial cells, however, GABA induces depolarization and triggers calcium-dependent signaling pathways. Müller glia, the principal retinal glial population, maintain retinal homeostasis and are the major source of neuroretinal VEGF-A, a key angiogenic factor in development and disease. Although GABA receptor (GABAR) activity has been proposed to influence retinal VEGF-A, it remains unclear whether this regulation occurs through Müller glial cells (MGC) and which mechanisms are involved. Here, we investigated how GABAR activation modulates VEGF-A in primary mouse MGC cultures. Cells were exposed to GABA and selective agonists or antagonists of GABA_A (muscimol, gabazine) and GABA_B receptors (baclofen, CGP55845). VEGF-A expression and secretion were analyzed by immunofluorescence, western blot, RT-qPCR, and ELISA. To assess Ca²⁺ involvement, we used Ca²⁺-free Ringer-Krebs solution and the L-type channel blocker nimodipine, and examined MAPK signaling with the ERK1/2 inhibitor FR180204. Our findings show that GABA and muscimol increased VEGF-A fluorescence intensity after 48 hours while reducing VEGF-A secretion, without altering Vegfa mRNA. Both effects were abolished by extracellular Ca²⁺ removal or nimodipine, indicating a Ca²⁺-dependent mechanism. FR180204 also attenuated GABA- and GABA_A-mediated effects, implicating MAPK signaling. Short-term assays revealed that GABA rapidly elevates VEGF-A protein and secretion within ∼30 minutes. Together, these findings identify a Ca²⁺- and GABA_A-dependent pathway through which Müller glia regulate VEGF-A production and release, providing new insight into glial signaling and neurotransmitter-driven modulation of retinal angiogenic factors.

Research on diabetic retinopathy (DR) usually emphasizes hyperglycemia and other causes like dyslipidemia, which are still not well understood. This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on Müller Glial Cell (MGC) dysfunction and angiogenic signaling. Primary MGC cultures were treated with G25 (25 mM), PA (250 µM), or PA + G25 for 24 and 48 h, followed by assessments of cell viability and analysis of the Vascular Endothelial Growth Factor (VEGFA)/VEGFA receptor 2 (VEGFR2) pathway through immunofluorescence, Western blot, and ELISA. Additionally, Gaussian mixture models (GMMs) were used to identify phenotypic subpopulations based on fluorescence intensity. The results showed that while hyperglycemia did not cause significant changes, PA and PA + G25 induced apoptosis-related cell death and significantly increased the expression of VEGFA, VEGFR2, HIF-α, and SP1. Although broad phenotypic diversity was observed at 24 h, by 48 h, a distinct shift towards an angiogenic phenotype was noted, with significantly elevated VEGFA/VEGFR2 levels. In summary, this research demonstrates that PA acts as a critical inducer of an angiogenic secretory phenotype in MGCs, indicating that lipid-mediated signaling plays a vital role in neovascularization in DR, possibly independent of glucose levels.

Type 2 diabetes mellitus (T2DM) is associated with increased cataract risk, potentially due to osmotic imbalance from intracellular sorbitol accumulation affecting lens cell volume regulation. To evaluate the expression of Kir4.1, TRPV4, and LRRC8A channels—key regulators of cell volume—in the anterior lens capsule of patients with and without T2DM. A cross-sectional observational study was conducted using anterior lens capsules from 50 patients undergoing cataract surgery (24 with T2DM, and 26 non-diabetic). Cataract severity was graded using the Lens Opacities Classification System III, and immunofluorescence was used to quantify protein expression. T2DM patients exhibited greater severity in cortical and nuclear cataracts, particularly among women. Diabetic samples showed increased Kir4.1 and decreased TRPV4 and LRRC8A expression. The study identifies associations between T2DM and altered expression of osmoregulatory proteins in the lens capsule, which may relate to the formation and severity of cataracts. These exploratory findings warrant further investigation to clarify underlying mechanisms.