Adhesion GPCR Latrophilin 3 regulates synaptic function of cone photoreceptors in a trans-synaptic manner

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 45; p. 1
• Main Authors: Wang, Yuchen, Cao, Yan, Hays, Cassandra L., Laboute, Thibaut, Ray, Thomas A., Guerrero-Given, Debbie, Ahuja, Abhimanyu S., Patil, Dipak, Rivero, Olga, Kamasawa, Naomi, Kay, Jeremy N., Thoreson, Wallace B., Martemyanov, Kirill A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.11.2021
• Subjects: Adhesion; Alternative Splicing; Animals; Biological Sciences; Calcium channels; Calcium channels (voltage-gated); Calcium Channels - metabolism; Channel gating; Cones; Dendrites; G protein-coupled receptors; Horizontal cells; Life Sciences; Mice; Mice, Knockout; Modulation; Negative feedback; Neurotransmitter release; Neurotransmitters; Photoreception; Photoreceptors; Protein Isoforms - metabolism; Proteome; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Retinal Cone Photoreceptor Cells - metabolism; Splicing; Synapses; Synapses - metabolism; Synaptic transmission; Vertebrates; adhesion GPCR; vision; synapses; retina; horizontal cells
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2106694118

This study addresses a fundamental question in neuroscience: how do neurons functionally specify and diversify their synaptic connections? This question is particularly relevant in the visual system in which neurons handle a broad range of stimuli requiring synapses to adjust their gain accordingly. In this work, we describe how synapses of cone photoreceptors, which all vertebrate animals utilize for daylight vision, handle this task through an elegant trans-synaptic mechanism involving a splice isoform of a cell-adhesion molecule, Latrophillin 3. Cone photoreceptors mediate daylight vision in vertebrates. Changes in neurotransmitter release at cone synapses encode visual information and is subject to precise control by negative feedback from enigmatic horizontal cells. However, the mechanisms that orchestrate this modulation are poorly understood due to a virtually unknown landscape of molecular players. Here, we report a molecular player operating selectively at cone synapses that modulates effects of horizontal cells on synaptic release. Using an unbiased proteomic screen, we identified an adhesion GPCR Latrophilin3 (LPHN3) in horizontal cell dendrites that engages in transsynaptic control of cones. We detected and characterized a prominent splice isoform of LPHN3 that excludes a element with inhibitory influence on transsynaptic interactions. A gain-of-function mouse model specifically routing LPHN3 splicing to this isoform but not knockout of LPHN3 diminished Ca V 1.4 calcium channel activity profoundly disrupted synaptic release by cones and resulted in synaptic transmission deficits. These findings offer molecular insight into horizontal cell modulation on cone synaptic function and more broadly demonstrate the importance of alternative splicing in adhesion GPCRs for their physiological function.