The hydrophobic amino acids in putative helix 8 in carboxy-terminus of histamine H3 receptor are involved in receptor-G-protein coupling

Atsuo Kuramasu, Jun Sukegawa, Takeya Sato, Eiko Sakurai, Takehiko Watanabe, Teruyuki Yanagisawa, Kazuhiko Yanai

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Functional roles of putative helix 8 in the carboxy-terminal tail of the human histamine H 3 receptor were investigated using deleted and alanine-substituted mutant receptors. While the deletion of the carboxy-terminal tail did not decrease the total expression level, surface expression, or ligand binding affinity, the agonist-stimulated cAMP response, [ 35S] GTPγS binding, and MAPK activation were totally abolished. The receptor lacking the carboxy-terminal tail also failed to respond to an inverse agonist, thioperamide, suggesting that the carboxy-terminal tail is involved in the regulation of receptor activity by changing G-protein coupling with the receptor. Site-directed mutagenesis revealed that hydrophobic amino acids in the putative helix 8 such as phenylalanines at position 419 (F7.60) and 423 (F7.64) or leucines at 426 (L7.67) and 427 (L7.68) were important for the agonist-induced activation of H 3 receptor. Substitution of F7.60 also resulted in a receptor that was less responsive to inactivation by the inverse agonist, implying the existence of an intermediate conformation that can be either activated or inactivated. Our results suggest that hydrophobic interface of putative helix 8 is important for the regulation of H 3 receptor activity, presumably by stabilizing the helix to the plasma membrane.

Original languageEnglish
Pages (from-to)1843-1849
Number of pages7
JournalCellular Signalling
Volume23
Issue number11
DOIs
Publication statusPublished - 2011 Nov

Keywords

  • G-protein coupled receptor
  • Helix 8
  • Histamine H3 receptor
  • Signaling

ASJC Scopus subject areas

  • Cell Biology

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