Schematic drawing of the proposed feedback mechanism.

<p>(A) The ephaptic mechanism. Cones continuously release glutamate in the dark via a ribbon (R) synapse optimized for sustained glutamate release. This release depends on the activity of presynaptic Ca²⁺ channels (red). HC dendrites end laterally to the cone synaptic ribbon. Cx hemichannels (green) and Panx1 channels (blue) are expressed on the dendrites of HCs. Because they are both nonspecific channels and are open at the physiological membrane potentials of HCs, a current will flow into the HCs. HC dendrites invaginate the cone synaptic terminal, which leads to a large extracellular resistance (white resistor). The current that flows into HCs via the Cx hemichannels and Panx1 channels has to pass this resistor, which will induce a slight negativity deep in the synaptic cleft. The result will be that the voltage-gated Ca²⁺ channels sense a slightly depolarized membrane potential. When HCs hyperpolarize, the current through the Cx hemichannels will increase and so will the negativity in the synaptic cleft leading to a further decrease of the potential sensed by the cone Ca²⁺ channels. This is the fast component of feedback. (B) The Panx1/ATP-mediated mechanism. Expanded view of the pre- and postsynaptic membranes of cones and HCs. ATP is released by HCs via Panx1 channels. Through a number of steps ATP is converted into inosine, protons, and a phosphate buffer with a pKa of 7.2. This makes the synaptic cleft acidic relative to the extrasynaptic medium (pH 7.6–7.8), which inhibits Ca²⁺ channels and shifts their activation potential to positive potentials. Closing the Panx1 channels prevents HCs from releasing ATP, thereby stopping the production of phosphate buffer, leading to an alkalization of the synaptic cleft. This alkalization disinhibits the Ca²⁺ channels and shifts their activation potential to negative potentials. This mechanism underlies the slow component of feedback. (C) Schematic representation of I_Ca of cones with and without feedback. The black trace shows the I_Ca of cones in the dark. The red trace shows I_Ca when only the ephaptic feedback is active, whereas the blue trace shows the I_Ca when both the ephaptic and Panx1/ATP-mediated feedback are active.