A single mutation in helix 8 enhances the angiotensin II type 1a receptor transport and signaling

Shu Zhu, Maoxiang Zhang, Jason E. Davis, William H. Wu, Kristen Surrao, Hong Wang, Guangyu Wu

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The amphipathic helix 8 in the membrane-proximal C-terminus is a structurally conserved feature of class A seven transmembrane-spanning G protein-coupled receptors (GPCRs). Mutations of this helical motif often cause receptor misfolding, defective cell surface transport and dysfunction. Surprisingly, we demonstrated here that a single point mutation at Lys308 in helix 8 markedly enhanced the steady-state surface density of the angiotensin II type 1a receptor (AT1aR). Consistent with the enhanced cell surface expression, Lys308 mutation significantly augmented AT1aR-mediated mitogen-activated protein kinase ERK1/2 activation, inositol phosphate production, and vascular smooth muscle cell migration. This mutation also increased the overall expression of AT1aR without altering receptor degradation. More interestingly, Lys308 mutation abolished AT1aR interaction with β-COP, a component of COPI transport vesicles, and impaired AT1aR responsiveness to the inhibition of Rab6 GTPase involved in the Golgi-to-ER retrograde pathway. Furthermore, these functions of Lys308 were largely dependent on its positively charged property. These data reveal previously unappreciated functions of helix 8 and novel mechanisms governing the cell surface transport and function of AT1aR.

Original languageEnglish (US)
Pages (from-to)2371-2379
Number of pages9
JournalCellular Signalling
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Angiotensin II receptor
  • G protein-coupled receptor
  • Signaling
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'A single mutation in helix 8 enhances the angiotensin II type 1a receptor transport and signaling'. Together they form a unique fingerprint.

  • Cite this