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The Journal of Neuroscience, February 1, 2003, 23(3):907

Role of the G-Protein-Coupled Receptor GPR12 as High-Affinity Receptor for Sphingosylphosphorylcholine and Its Expression and Function in Brain Development

Atanas Ignatov^{1, *}, Julia Lintzel^{1, *}, Irm Hermans-Borgmeyer¹, Hans-Jürgen Kreienkamp², Patrick Joost³, Susanne Thomsen³, Axel Methner³, and H. Chica Schaller¹

¹ Zentrum für Molekulare Neurobiologie Hamburg, ² Institut für Zellbiochemie und klinische Neurobiologie, and ³ Klinik für Neurologie, Universität Hamburg, D-20246 Hamburg, Germany

Lysophospholipids are bioactive molecules influencing numerous cellular processes such as proliferation, differentiation, and motility. As extracellular ligands, they interact with specific members of the G-protein-coupled receptor family. We show in this paper that the lysophospholipid sphingosylphosphorylcholine is a high-affinity ligand for the orphan G-protein-coupled receptor GPR12. Heterologous expression of GPR12 in Chinese hamster ovary cells and in frog oocytes revealed a high-affinity interaction with sphingosylphosphorylcholine in the nanomolar range. Blockade of its action by pertussis toxin was taken as evidence that GPR12 is coupled to an inhibitory G-protein. In the adult mouse brain, GPR12 was expressed in the limbic system. During mouse embryonal development, GPR12 transcripts were detected in the CNS, especially in areas where neuronal differentiation occurs. Consistent with this we found that cultures of embryonal cerebral cortical neurons responded to sphingosylphosphorylcholine with an increase in synaptic contacts. The GPR12-expressing hippocampal cell line HT22 reacted to sphingosylphophorylcholine with an increase in cell proliferation and cell clustering. Other receptors known to interact at nanomolar concentrations with sphingosylphosphorycholine were expressed neither in the developing cerebral cortex nor in the HT22 cell line. We therefore hypothesize that sphingosylphosphorylcholine, most likely by interaction with GPR12, has positive effects on the differentiation and maturation of postmitotic neurons and that it may also influence the proliferation of neuronal precursor cells.

Key words: G-protein-coupled receptor; GPR12; lysophospholipid receptor; SPC; S1P; cerebral cortex development; HT22 cells

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^* A.I. and J.L. contributed equally to this work.

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Copyright © 2003 Society for Neuroscience  0270-6474/03/233907-08$05.00/0

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