Discovery of a Novel Member of the Histamine Receptor Family

  1. Tuan Nguyen1,
  2. David A. Shapiro4,
  3. Susan R. George1,2,3,
  4. Vincent Setola4,
  5. Dennis K. Lee2,
  6. Regina Cheng1,
  7. Laura Rauser5,
  8. Samuel P. Lee2,
  9. Kevin R. Lynch6,
  10. Bryan L. Roth4,5 and
  11. Brian F. O'Dowd1,2
  1. 1The Centre for Addiction and Mental Health, Toronto, Ontario, Canada (T.N., S.R.G., R.C., B.F.O.); Departments of 2Pharmacology (S.R.G., D.K.L., S.P.L., B.F.O.) and 3Medicine (S.R.G.), University of Toronto, Toronto, Ontario, Canada; 4Department of Biochemistry (D.A.S., V.S., B.L.R.) and 5National Institute of Mental Health Psychoactive Drug Screening Program (L.R., B.L.R.), Case Western Reserve University Medical School, Cleveland, Ohio; and 6Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia (K.R.L).

    Abstract

    We report the discovery, tissue distribution and pharmacological characterization of a novel receptor, which we have named H4. Like the three histamine receptors reported previously (H1, H2, and H3), the H4 receptor is a G protein-coupled receptor and is most closely related to the H3 receptor, sharing 58% identity in the transmembrane regions. The gene encoding the H4 receptor was discovered initially in a search of the GenBank databases as sequence fragments retrieved in a partially sequenced human genomic contig mapped to chromosome 18. These sequences were used to retrieve a partial cDNA clone and, in combination with genomic fragments, were used to determine the full-length open reading frame of 390 amino acids. Northern analysis revealed a 3.0-kb transcript in rat testis and intestine. Radioligand binding studies indicated that the H4 receptor has a unique pharmacology and binds [3H]histamine (Kd = 44 nM) and [3H]pyrilamine (Kd = 32 nM) and several psychoactive compounds (amitriptyline, chlorpromazine, cyproheptadine, mianserin) with moderate affinity (Ki range of 33–750 nM). Additionally, histamine induced a rapid internalization of HA-tagged H4 receptors in transfected human embryonic kidney 293 cells.

    Footnotes

    • Send reprint requests to: Dr. Brian F. O'Dowd, Department of Pharmacology, University of Toronto, Medical Science Building, 8 Taddle Creek Rd. Rm 4353, Toronto, Ontario, Canada M5S 1A8. E-mail:brian.odowd{at}utoronto.ca

    • This research was funded by the Canadian Institutes of Health Research (B.F.O. and S.R.G.), the National Institute on Drug Abuse (B.F.O. and S.R.G.), and in part by K02-MH01366 and N01–80005 to B.L.R.

    • T.N. and D.A.S. contributed equally to this work.

    • Abbreviations:
      GPCR(s)
      G protein-coupled receptor(s)
      HTGS
      high-throughput genomic sequence
      TM
      transmembrane
      NCBI
      National Center for Biotechnology Information
      PCR
      polymerase chain reaction
      HA
      hemagglutinin
      HEK
      human embryonic kidney cells
      kb
      kilobase pair
      • Received October 4, 2000.
      • Accepted January 5, 2001.
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    1. Molecular Pharmacology March 1, 2001 vol. 59 no. 3 427-433
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