Amacrine cells are interneurons that have diverse functions in retinal signal processing. In order to study signaling and modulation in retinal amacrine cells, we employ a simplified culture system containing identifiable GABAergic amacrine cells. Immunocytochemistry experiments indicate that GABAergic amacrine cells express metabotropic glutamate receptor 5 (mGluR5), a group I mGluR usually linked to the IP3 signaling pathway. Ca² imaging experiments using an mGluR5-specific agonist indicate that these receptors are functional and when activated, can stimulate temporally diverse Ca² elevations. To begin to establish the role of these receptors in modulating amacrine cell function, we have used electrophysiological methods to ask whether ion channels are the targets of mGluR5-dependent modulation. Here we discuss our results indicating that activation of mGluR5 leads to enhancement of currents through GABA_A receptors. This enhancement is dependent upon elevations in cytosolic Ca² and activation of protein kinase C (PKC). To explore the consequences of Ca² elevations in another context, we have used nitric oxide (NO) donors to mimic the effects of activating the Ca² -dependent synthetic enzyme for NO, neuronal nitric oxide synthase. We find that exposure to NO donors also enhances the amplitude of currents through GABA_A receptors. Together, these results indicate that glutamate from presynaptic bipolar cells has the potential to work through multiple mechanisms to regulate the function of amacrine-to-amacrine cell GABAergic synapses.