The orphan G protein-coupled receptor GPR56 is highly-expressed in neural stem cells (NSCs), and mutations in GPR56 cause disordered brain development in humans. The key role that GPR56 plays in NSC function makes it an attractive target for therapeutics that might be capable of highly-selective NSC modulation. However, little is currently known about the fundamental properties of GPR56. The specific targeting of GPR56 by therapeutics will require a more comprehensive understanding of the molecular mechanisms controlling receptor activation, regulation and localization. We will therefore study the mechanism of activation for GPR56, examining in particular the issue of whether shedding of the N-terminus (NT) is involved in receptor activation. We will also study the factors controlling GPR56-NT shedding, as well as whether receptor activation can be influenced by NT-binding peptides. Furthermore, we will assess the regulation of GPR56 activity by cytoplasmic binding partners of the receptor that have been identified in preliminary work, including beta-arrestins and PDZ scaffolds. Finally, we will study the factors controlling GPR56 localization in NSCs and other cell types, with a particular emphasis on determining the importance of receptor targeting to cilia. In addition to providing insights about the fundamental properties of GPR56, these studies will lay the groundwork for targeting GPR56 as a means of selectively modulating NSC function in the treatment of various neurodevelopmental and neurodegenerative diseases.
The modulation of neural stem cells is a promising therapeutic approach in the treatment of various neurodevelopmental and neurodegenerative diseases. The orphan G protein-coupled receptor GPR56 is highly-expressed in neural stem cells and is therefore an attractive target for therapeutics that might be capable of highly-selective modulation of neural stem cell function. The proposed project will study GPR56 activation and regulation to lay the groundwork for potential therapeutic targeting of this receptor, which is expressed in neural stem cells.
|Kishore, Ayush; Hall, Randy A (2017) Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling. J Biol Chem 292:9711-9720|
|Kishore, Ayush; Purcell, Ryan H; Nassiri-Toosi, Zahra et al. (2016) Stalk-dependent and Stalk-independent Signaling by the Adhesion G Protein-coupled Receptors GPR56 (ADGRG1) and BAI1 (ADGRB1). J Biol Chem 291:3385-94|
|Liebscher, Ines; Ackley, Brian; Araç, Demet et al. (2014) New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors. Ann N Y Acad Sci 1333:43-64|
|Stephenson, Jason R; Purcell, Ryan H; Hall, Randy A (2014) The BAI subfamily of adhesion GPCRs: synaptic regulation and beyond. Trends Pharmacol Sci 35:208-15|
|Stephenson, Jason R; Paavola, Kevin J; Schaefer, Stacy A et al. (2013) Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density. J Biol Chem 288:22248-56|
|Paavola, Kevin J; Hall, Randy A (2012) Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation. Mol Pharmacol 82:777-83|
|Paavola, Kevin J; Stephenson, Jason R; Ritter, Stefanie L et al. (2011) The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. J Biol Chem 286:28914-21|