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Characterization of GPRA, a Novel G Protein–Coupled Receptor Related to Asthma

Department of Medical Genetics, and Department of Anatomy, Biomedicum Helsinki, Department of Pathology, Haartman Institute, University of Helsinki; GeneOS Ltd.; and Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; and Department of Biosciences at Novum and Clinical Research Centre, Karolinska Institutet, Huddinge, Sweden

Correspondence and requests for reprints should be addressed to Tarja Laitinen, GeneOS Ltd., Tukholmankatu 2, 00251 Helsinki, Finland. E-mail: tarja.laitinen{at}geneos.fi

We recently identified a novel positional asthma susceptibility gene, GPRA, which belongs to the G protein-coupled receptor family. In the present studies, we show that isoform specific activation of GPRA-A with its agonist, Neuropeptide S (NPS) resulted in significant inhibition of cell growth. GPRA has several variants due to extensive alternative splicing. We observed that only the full-length variants, GPRA-A and GPRA-B, with 7 transmembrane topology are transported into the plasma membrane, while the truncated proteins retain intracellular compartments. To clarify disease mechanism, we studied co-expression of the variants without finding any indication that truncated variants would inhibit the receptor transport into the plasma membrane. By using in situ hybridization and immunohistochemistry, we detected ubiquitous expression of GPRA-B, and frequent expression of GPRA-A in the epithelia of several organs including bronchi and gastrointestinal tract. Furthermore, we observed aberrant mRNA and protein expression levels of GPRA in the asthmatic bronchi. Finally, we demonstrate that GPRA and NPS are co-expressed in bronchial epithelium. In summary, this study provides evidence that GPRA might have functional relevance in modulating asthma by increased expression levels in the relevant tissues under diseased state and by potential inhibitory effect of GPRA-A activation on cell growth.

Key Words: asthma • susceptibility • GPRA • G protein–coupled receptor • Neuropeptide S

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