Histamine H2 Receptor Mediated Dual Signaling: Mapping of Structural Requirements Using β2 Adrenergic Chimeric Receptors

doi:10.1006/bbrc.2000.3507

Biochemical and Biophysical Research Communications

Volume 276, Issue 2, 24 September 2000, Pages 539-545

https://doi.org/10.1006/bbrc.2000.3507 Get rights and content

Abstract

Previously we demonstrated that the histamine H2 receptor can activate both the adenylate cyclase and phosphoinositide/protein kinase (PKC) signaling pathways. Although dual coupling occurs via separate GTP-dependent mechanisms the structural components of the H2 receptor directing differential signaling have not been established. We explored this question by attempting to confer to the β2-adrenergic receptor (βAR), which is known to stimulate cAMP formation, the ability to activate PKC through the construction of β2/H2 chimeric receptors. Intracytoplasmic domains of the human β2 adrenergic receptor were substituted with the corresponding sequences of the human H2 receptor and stably expressed in HEK-293 cells. Binding of [³H]-CGP to chimeric wild type β2 receptors was comparable. Substitution of the second intracellular loop (2i) of the βAR led to a significant decrease in coupling to adenylate cyclase while leading to a 139.5 ± 9.4% control increase in epinephrine mediated PKC activation. Introduction of the H2 receptor 3i also led to a decrease in βAR mediated cAMP generation but provided the latter with the ability to stimulate PKC (182.2 ± 8% of control). Concomitant expression of both 2i and 3i led to a substantial increase in epinephrine mediated PKC activation (201.8 ± 10.5% of control). Addition of the carboxyl terminal tail did not facilitate stimulation of PKC. In summary, the third intracellular loop of the H2 receptor plays an essential role in activating PKC with maximal efficiency conferred by the second intracellular domain.

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Activation of H2R leads to adenylyl cyclase activation and elevation of intracellular cAMP concentration [29–31]. Furthermore, an additional Gq-protein-mediated pathway has been described [32,33]. Numerous compounds which agonize or antagonize the H2R have been synthesized [34] and H2R antagonists are used for the treatment of acid-related gastrointestinal diseases [35].
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Histamine-mediated activation of the H2 receptor subtype, in particular, can result in the activation of both adenylyl cyclase and PLC second messenger systems [15]. The structural components of the human H2 receptor required to activate adenylyl cyclase and PLC systems have been elucidated recently, but the physiological significance of H2 receptor coupling to PLC activation has not been totally clarified [38]. However, several reports have suggested that the H2 receptor-mediated activation of PLC and intracellular calcium mobilization could influence cell proliferation [39,40].
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¹: To whom correspondence should be addressed at 6520 MSRBI, Box 0682, University of Michigan Medical School, Ann Arbor, MI 48109. Fax: (734) 763-2535. E-mail: [email protected].

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Regular ArticleHistamine H2 Receptor Mediated Dual Signaling: Mapping of Structural Requirements Using β2 Adrenergic Chimeric Receptors

Abstract

Biochim. Biophys. Acta

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J. Biol. Chem.

J. Biol. Chem.

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Eur. J. Pharmacol.

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Cell Signal

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Regular Article
Histamine H2 Receptor Mediated Dual Signaling: Mapping of Structural Requirements Using β2 Adrenergic Chimeric Receptors