Fig. 2

Signaling pathways that control coupling in two types of retinal neuron. Coupling through Cx36 gap junctions is regulated by Cx36 phosphorylation through an order of magnitude dynamic range. Phosphorylation enhances coupling and pathways that promote Cx36 phosphorylation are colored green in this diagram while those that reduce phosphorylation are colored red. Elements colored blue are hypothesized to play a role but have not been specifically demonstrated. a Retinal AII amacrine cell coupling is increased by Cam Kinase II phosphorylation driven by Ca²⁺ influx through non-synaptic NMDA-type glutamate receptors. This process depends on spillover glutamate derived from bipolar cells and is enhanced by activation of synaptic AMPA-type glutamate receptors that depolarize the cell. Reduction of Cx36 phosphorylation is driven by an independent pathway in which activation of D1 dopamine receptors increases adenylyl cyclase activity, activating protein kinase A, which in turn activates protein phosphatase 2A. Protein phosphatase 1 suppresses this pathway. Both pathways are activated by light, but with different thresholds, leading to an inverted U-shaped light adaptation curve. b Photoreceptor coupling is enhanced by Cx36 phosphorylation driven directly by protein kinase A activity under control of adenylyl cyclase (AC). AC activity is in turn controlled by an intricate set of G-protein coupled receptors regulated by circadian time and light adaptation. Darkness during the night phase increases extracellular adenosine such that activation of A2a adenosine receptors dominates signaling and activates AC. Light adaptation or subjective daytime result in reduced extracellular adenosine and increased dopamine secretion such that activation of dopamine D4 receptors dominates signaling to suppress AC activity. A1 adenosine receptors supplement this effect. The opposing signaling pathways routed through a common effector impart a steep monophasic character to the light adaptation and circadian control of coupling in this neural network