The Journal of biological chemistry
-
Nogo, MAG, and OMgp are myelin-associated proteins that bind to a neuronal Nogo-66 receptor (NgR/NgR1) to limit axonal regeneration after central nervous system injury. Within Nogo-A, two separate domains are known interact with NgR1. NgR1 is the founding member of the three-member NgR family, whereas Nogo-A (RTN4A) belongs to a four-member reticulon family. ⋯ To better define how these multiple structurally distinct ligands bind to NgR1, we examined a series of Ala-substituted NgR1 mutants for ligand binding activity. We found that the core of the binding domain is centered in the middle of the concave surface of the NgR1 leucine-rich repeat domain and surrounded by differentially utilized residues. This detailed knowledge of the molecular interactions between NgR1 and its ligands is imperative when assessing options for development of NgR1-based therapeutics for central nervous system injuries.
-
Lysophosphatidic acid (LPA) is a potent lipid mediator that evokes a variety of biological responses in many cell types via its specific G protein-coupled receptors. In particular, LPA affects cell morphology, cell survival, and cell cycle progression in neuronal cells. Recently, we identified p2y(9)/GPR23 as a novel fourth LPA receptor, LPA(4) (Noguchi, K., Ishii, S., and Shimizu, T. (2003) J. ⋯ In LPA(4) transfectants, LPA induced dramatic morphological changes, i.e. neurite retraction, cell aggregation, and cadherin-dependent cell adhesion, which involved Rho-mediated signaling pathways. Thus, our results demonstrated that LPA(4) as well as LPA(1) couple to G(q/11) and G(12/13), whereas LPA(4) differs from LPA(1) in that it does not couple to G(i/o). Through neurite retraction and cell aggregation, LPA(4) may play a role in neuronal development such as neurogenesis and neuronal migration.
-
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that signals through G protein-coupled receptors (GPCRs) to produce a range of biological responses. A recently reported fourth receptor, LPA(4)/GPR23, was notable for its low homology to the previously identified receptors LPA(1-3) and for its ability to increase intracellular concentrations of cAMP and calcium. However, the signaling pathways leading to LPA(4)-mediated induction of cAMP and calcium levels have not been reported. ⋯ The receptor is broadly expressed in embryonic tissues, including brain, as determined by Northern blot and reverse transcription-PCR analysis. Adult tissues have increased expression in skin, heart, and to a lesser extent, thymus. These data confirm the identification and extend the functionality of LPA(4) as an LPA receptor, bringing the number of independently verified LPA receptors to five, with both overlapping and distinct signaling properties and tissue expression.