The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease

Abstract

Our robust visual experience is based on the reliable transfer of information from our photoreceptor cells, the rods and cones, to higher brain centers. At the very first synapse of the visual system, information is split into two separate pathways, ON and OFF, which encode increments and decrements in light intensity, respectively. The importance of this segregation is borne out in the fact that receptive fields in higher visual centers maintain a separation between ON and OFF regions. In the past decade, the molecular mechanisms underlying the generation of ON signals have been identified, which are unique in their use of a G-protein signaling cascade. In this review, we consider advances in our understanding of G-protein signaling in ON-bipolar cell (BC) dendrites and how insights about signaling have emerged from visual deficits, mostly night blindness. Studies of G-protein signaling in ON-BCs reveal an intricate mechanism that permits the regulation of visual sensitivity over a wide dynamic range.

Keywords: ON-bipolar neurons; regulators of G-protein signaling; scaffolding; signal transduction; synaptic transmission.

Figure 1. Organization of the first visual synapse between photoreceptors and ON-bipolar cells

Changes in glutamate release by photoreceptors are detected by the signaling cascade initiated by the mGluR6 receptor.

Figure 2. A model for TRPM1 channel gating by G proteins

Direct binding of both activated Gαo-GTP and Gβγ subunits to the cytoplasmic domains of the TRPM1 channel keep it in closed state. Upon GTP hydrolysis, G proteins rearrange forming inactive heterotrimer allowing the TRPM1 channel to open. Modified from (Xu et al. 2016).

Figure 3. Organization of the GAP complex of ON-bipolar cells

Multiple subunits bind together through direct protein-protein interactions to form a single unit that promotes GTP hydrolysis on its G protein substrate, Gαo. PGL, PDEγ-like domain that scaffolds Gαo-GTP.

Figure 4. Scaffolding of multiple components of the ON-BC cascade into a single “signalosome” unit

The components of the cascade are linked together through physical interactions that promote the efficiency of signal transduction.

Figure 5. Trans-synaptic integration of ON-bipolar transduction cascade

Components of mGluR6 interact with multiple cell-adhesion and extracellular matrix proteins present at the synapse.

Figure 6. Mutations in multiple synaptic molecules at the first visual synapse are associated with human disease

Diagram depicts pre- versus post-synaptic position of signaling molecules and their corresponding genes. Further, the genes implicated in disorders featuring visual deficits are identified.