Functional characterization of the orphan aGPCR VLGR1/GPR98 in health and disease
Uwe Wolfrum, University of Mainz
The very large G protein-coupled receptor-1 (VLGR1), also known as MASS1, GPR98 or USH2C protein, is by far the largest GPCR of our body. It is composed of an extremely long N-terminal extracellular domain (ECD) composed of modular adhesion domains, the 7-transmembrane domain and a short cytoplasmic intracellular C-terminus (ICD) which terminates in a PDZ-binding motif. VLGR1 is expressed in form of numerous alternatively spliced isoforms, including MASS1 isoforms, VLGR1a and 1b. In the absence of any known ligand, VLGR1 is one of the few adhesion-GPCRs in which mutations are disease-relevant. Mouse vlgr1 mutants are characterized by the susceptibility to audiogenic seizures but also develop sensorineural defects, namely hearing loss and visual dysfunction. In humans, mutations in the VLGR1/GPR98 gene cause Usher syndrome USH2C, a subtype of the most common form of combined hereditary deaf-blindness.
We and others have identified VLGR1 as a component of USH protein networks interacting with USH scaffold proteins in inner ear and retina. In hair cells, VLGR1 is part of the ankle link complexes which are essential for the correct development of the mechano-sensitive hair bundles. In photoreceptor cells VLGR1 is a component of the periciliary USH protein network crucial for cargo transport to the photoreceptor cilium. In the latter adhesion complex VLGR1 is required for the assembly of fibres linking the membranes of the inner segment and the photoreceptor cilium. In both sensory systems VLGR1 is additionally found at synapses.
In the present project we will focus on following scientific objectives: (1) Elucidation of the cellular machineries associated with VLGR1 by defining specific partners in vitro and in vivo, (2) deciphering of the downstream signaling pathway initiated via VLGR1 activation, and (3) analysis of the VLGR1 adhesion function. We are confident that the results of the proposed enterprise will enlighten how the aGPCR VLGR1 signals and how the molecular machineries related to the cellular operation of VLGR1 function, which will certainly contribute to understanding not only common features of aGPCRs, but also the pathomechanisms underlining the sensoneu-ronal degenerative Usher disease. Identification of the signaling pathways connected to VLGR1 may also provide therapeutic targets for the cure of the sensoneuronal degenerations in Usher syndrome patients which are currently not treatable.
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