Characterization of GPRA, a novel G protein-coupled receptor related to asthma.

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.

[1]  S. Weiland,et al.  G-Protein-coupled receptor polymorphisms are associated with asthma in a large German population. , 2005, American journal of respiratory and critical care medicine.

[2]  C. Lindgren,et al.  Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma. , 2005, American journal of respiratory and critical care medicine.

[3]  S. Henriksen,et al.  Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. , 2004, Neuron.

[4]  Thomas J. Hudson,et al.  Characterization of a Common Susceptibility Locus for Asthma-Related Traits , 2004, Science.

[5]  Maree H. Poniris,et al.  Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism. , 2004, The Journal of allergy and clinical immunology.

[6]  G. Cutler,et al.  Elucidation of signaling properties of vasopressin receptor-related receptor 1 by using the chimeric receptor approach. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  I. Adcock,et al.  Allergen‐induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N‐terminal kinase , 2003, British journal of pharmacology.

[8]  K. Rabe,et al.  Proliferation and inflammation in bronchial epithelium after allergen in atopic asthmatics , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[9]  M. Mortrud,et al.  The G protein-coupled receptor repertoires of human and mouse , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  H. Vaudry,et al.  Novel Splice Variants of Type I Pituitary Adenylate Cyclase-Activating Polypeptide Receptor in Frog Exhibit Altered Adenylate Cyclase Stimulation and Differential Relative Abundance. , 2002, Endocrinology.

[11]  M. Daly,et al.  A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population , 2001, Nature Genetics.

[12]  R. Maki,et al.  Characterization of γ-Aminobutyric Acid Receptor GABAB(1e), a GABAB(1) Splice Variant Encoding a Truncated Receptor* , 2000, The Journal of Biological Chemistry.

[13]  T. Gudermann,et al.  Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor. , 1997, Molecular endocrinology.

[14]  G. Vogt,et al.  The two isoforms of the mouse somatostatin receptor (mSSTR2A and mSSTR2B) differ m coupling efficiency to adenylate cyclase and in agonist‐induced receptor desensitization , 1993, FEBS letters.

[15]  P. Insel,et al.  Genetic variations and polymorphisms of G protein-coupled receptors: functional and therapeutic implications. , 2001, Annual review of pharmacology and toxicology.

[16]  R. Ahn,et al.  Inhibitory activity of alternative splice variants of the bullfrog GnRH receptor-3 on wild-type receptor signaling. , 2001, Endocrinology.