| Adenosine activation of G protein-coupled receptors plays an important role in neuromodulation and neuroprotection throughout the central nervous system. In the brain, adenosine acts both pre and postsynaptically and can increase or decrease neuronal excitation through several different mechanisms. Presynaptically, adenosine alters neurotransmission by activating either A1 receptors to decrease neurotransmitter release or A 2A receptors to potentiate neurotransmitter release. The inhibitory presynaptic effects of A1 receptors are observed in the laterodorsal tegmentum, hippocampus, hypothalamus, nucleus accumbens, and the barrel cortex These effects are generally attributed to A1-mediated inhibition of N-type Ca2+ channels. Presynaptic A2A receptor-mediated facilitation of neurotransmitter release has also been described in several CNS regions, including the nucleus accumbens, hippocampus, superior colliculus, and the habenula. Increased neurotransmitter release is largely mediated by the A2A receptor-induced activation of P-type Ca2+ channels. Postsynaptically, adenosine activates A1 receptors that are linked to G protein-coupled inwardly rectifying K+ (GIRK) channels. Adenosine-evoked hyperpolarizing currents have been demonstrated in the hippocampus, the laterodorsal tegmentum, and the supraoptic nucleus.;In the retina, adenosine contributes to the modulation of retinal ganglion cell activity. In isolated ganglion cells of the rat retina, A1 receptor activation inhibits voltage-gated calcium channels. In addition, I have reported that stimulating retinal glial cells of the rat results in the generation of an adenosine-mediated inhibitory current in ganglion cells. Stimulated glial cells release ATP which is rapidly converted to adenosine by ectoenzymes. The adenosine activates receptors on the ganglion cells, resulting in cell hyperpolarization mediated by the opening of K+ channels. However, the intracellular signaling mechanisms responsible for this adenosine-evoked inhibition of retinal ganglion cells have not been elucidated.;In this work, I examine adenosine modulation of retinal ganglion cells in the rat retina. I have investigated which subtypes of adenosine receptors and which ion channels mediate the adenosine-evoked hyperpolarization of ganglion cells. I find that the adenosine response is mediated by A1 receptor activation of two distinct K+ channels: GIRK channels and small conductance Ca2+-activated K+ (SK) channels. The prolonged SK channel activation I observe, mediated by the A1-induced release of Ca2+ from intracellular stores, has not been previously described. |
