Orphan receptors organizing trans‐synaptic complexes: The case of GPR179 in the retina
Authors: Orlandi Cesare , Omori Yoshihiro , Wang Yuchen , Cao Yan , Ueno Akiko , Condomitti Giuseppe , De Wit Joris , Furukawa Takahisa , Martemyanov Kirill 
Published: June 2021

One of the defining properties of the central nervous system is the ability of establishing precise synaptic contacts between neurons. This process involves trans‐synaptic interactions between a host of cell‐adhesion molecules, membrane receptors and secreted ligands that act in cooperation with the extracellular matrix to specify unique physiological properties of individual synapses. Traditionally, members of the G protein‐coupled receptor (GPCR) family have been considered as powerful modulators of neurotransmission that shape properties of neuronal circuits. However, emerging proteomic studies increasingly point to their role in establishing trans‐synaptic connections and interactions with the extracellular matrix. Such effects were primarily shown for the subfamily of adhesion GPCRs but the scope and extent of conservation across the GPCR superfamily is yet to be explored. Moreover, the function and signaling properties of several GPCRs remain poorly understood, with many receptors still orphan of an endogenous ligand. Nonetheless, the identification of disease‐causing mutations in patients and the analysis of transgenic models suggest that many orphan receptors have essential physiological roles and represent an attractive druggable target. Our progress in de‐orphanizing these receptors and understanding their physiology has been slow, likely because of their unusual biology that may deviate from the traditional role of GPCRs as mediators of neurotransmitter signaling.In this study, we identify major components of the extracellular matrix in the synaptic cleft ‐ members of the Heparan Sulfate Proteoglycan (HSPG) family ‐ as binding partners of the orphan GPCRs, GPR179 and GPR158, and demonstrate an essential role of these interactions in synaptic targeting. Using the mammalian retina as a model we provide evidence that the photoreceptor‐released HSPG Pikachurin interacts with the orphan receptor GPR179 at the specific synapse between photoreceptors and ON‐bipolar neurons. We further demonstrate that this organization dictates the post‐synaptic targeting of the GAP complex by anchoring GPR179‐RGS at the dendritic tips of downstream ON‐bipolar neurons. Based on our observations we propose a model where Pikachurin, through its C‐terminal EGF‐like, Laminin G domain and HS side chains, acts as a bridge to connect the pre‐synaptic Dystroglycan‐Dystrophin complex at the photoreceptor axonal terminals with the extracellular domain of GPR179 on the post‐synaptic site. Here GPR179 recruits cytoplasmic RGS proteins that are essential for specifying temporal properties of the synaptic transmission in response to light. Finally, using in vivo retina electroporation and several transgenic animal models, we confirm that ablation of single components of this trans‐synaptic complex alters the post‐synaptic recruitment of RGS proteins affecting the neurotransmission of photoreceptors.Support or Funding InformationSupported by NIH grants EY018139, EY028033, and MH105482This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.