Presynaptic Expression of LRIT3 Transsynaptically Organizes the Postsynaptic Glutamate Signaling Complex Containing TRPM1
Nazarul Hasan,
Gobinda Pangeni,
Catherine A. Cobb,
Thomas A. Ray,
Emily R. Nettesheim,
Kristina J. Ertel,
Daniel M. Lipinski,
Maureen A. McCall,
Ronald G. Gregg
Affiliations
Nazarul Hasan
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40292, USA
Gobinda Pangeni
Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40292, USA
Catherine A. Cobb
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40292, USA
Thomas A. Ray
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40292, USA
Emily R. Nettesheim
Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Kristina J. Ertel
Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Daniel M. Lipinski
Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford OX3 9DU, UK
Maureen A. McCall
Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40292, USA; Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA
Ronald G. Gregg
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40292, USA; Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40292, USA; Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA; Corresponding author
Summary: Throughout the CNS, interactions between pre- and postsynaptic adhesion molecules establish normal synaptic structure and function. Leucine-rich repeat (LRR) domain-containing proteins are a large family that has a diversity of ligands, and their absence can cause disease. At the first retinal synapse, the absence of LRIT3 expression leads to the disassembly of the postsynaptic glutamate signaling complex (signalplex) expressed on depolarizing bipolar cell (DBC) dendrites. The prevalent view is that assembly of the signalplex results from direct postsynaptic protein:protein interactions. In contrast, we demonstrate that LRIT3 is expressed presynaptically, in rod photoreceptors (rods), and when we restore LRIT3 expression in Lrit3−/− rods, we restore expression of the postsynaptic glutamate signalplex and rod-driven vision. Our results demonstrate that, in the retina, the LRR-containing protein LRIT3 acts as a transsynaptic organizer of the postsynaptic complex required for normal synaptic function. : The leucine-rich repeat-containing protein LRIT3 is required for dim-light vision and postsynaptic signalplex assembly. Hasan et al. show that LRIT3 is expressed in rod photoreceptors and acts transsynaptically to localize the TRPM1 channel in the postsynaptic membrane. LRIT3 expression in knockout mice restores retinal function. Keywords: Lrit3, congenital stationary night blindness, rod photoreceptors, retina, bipolar cells, retinal ganglion cells, transsynaptic interactions, LRR proteins, TRPM1, mGluR6, CSNB
