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OtherGASTROINTESTINAL PHARMACOLOGY

Characterization of the Histamine H2 Receptor Structural Components Involved in Dual Signaling

L-D. Wang, M. Hoeltzel, I. Gantz, R. Hunter and J. Del Valle
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 573-578;
L-D. Wang
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M. Hoeltzel
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I. Gantz
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R. Hunter
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J. Del Valle
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Abstract

We previously demonstrated that the histamine H2 receptor can activate both adenylate cyclase (AC) and phospholipase C (PLC) signaling pathways via separate GTP- dependent mechanisms. We examined whether H2 receptor-specific peptides corresponding to the amino (N) or carboxyl terminus (C) of the second (2i) or third (3i) intracytoplasmic loops or the carboxyl terminal tail (P4iN) could effect histamine- stimulated AC and PLC activity in cell membranes prepared from HEPA cells stably transfected to express the canine H2 histamine receptor cDNA. Tiotidine binding and basal signaling were not altered by the synthetic peptides. H2P2iN, H2P2iC, H2P3iN and H2P4iN did not effect histamine stimulated AC activity although H2P3iC (10−4 M) significantly inhibited this parameter (65.6 ± 7.2% of maximal stimulation) (n = 6). Combination of the five peptides (H2P2iN, H2P2iC, H2P3iN, H2P3iC and H2P4iN) abolished histamine stimulated AC activity. Although all of the peptides inhibited histamine-stimulated PLC activity to a moderate degree individually, H2P3iC (10−4 M) had the greatest effect, decreasing PLC activation to 20.8 ± 6.3% of maximal stimulation (IC50 = 7.5 × 10−7 M) (n = 6). H2P3iC and the peptide combination did not alter, forskolin, GTPγs or epinephrine-stimulated AC activity nor GTPγs and vasopressin-stimulated PLC. These studies demonstrate that both the second and third intracytoplasmic loops of the histamine H2 receptor are linked to separate signaling pathways in a differential manner.

Footnotes

  • Send reprint requests to: Dr. John Del Valle, Division of Gastroenterology, University of Michigan, MSRB-I, Box 0682, Ann Arbor, MI 48109.

  • ↵1 This work was supported by the National Institutes of Health (NIH Grant RO1DK47434 and funds from the University of Michigan Gastrointestinal Peptide Research Center (NIH Grant P30DK34933). I.G. is the recipient of a VA Merit Award.

  • Abbreviations:
    AC
    adenylate cyclase
    PLC
    phospholipase C
    N
    amino
    C
    carboxyl
    G-protein
    guanine nucleotide binding protein
    BSA
    bovine serum albumin
    DTT
    dithiotreitol
    EBSS. Earle’s balanced salt solution
    HPLC, high-performance liquid chromatography
    AVP
    vasopressin
    AT2R1
    angiotensin II type 1 receptor
    PAFR
    platelet-activating factor receptor
    PI
    phosphoinositide
    • Received September 10, 1997.
    • Accepted January 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherGASTROINTESTINAL PHARMACOLOGY

Characterization of the Histamine H2 Receptor Structural Components Involved in Dual Signaling

L-D. Wang, M. Hoeltzel, I. Gantz, R. Hunter and J. Del Valle
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 573-578;

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OtherGASTROINTESTINAL PHARMACOLOGY

Characterization of the Histamine H2 Receptor Structural Components Involved in Dual Signaling

L-D. Wang, M. Hoeltzel, I. Gantz, R. Hunter and J. Del Valle
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 573-578;
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