Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex

Leo T O Lee, Stephanie Y L Ng, Jessica Y S Chu, Revathi Sekar, Kaleeckal G. Harikumar, Laurence J Miller, Billy K C Chow

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Angiotensin (ANGII) and secretin (SCT) share overlapping, interdependent osmoregulatory functions in brain, where SCT peptide/receptor function is required for ANGII action, yet the molecular basis is unknown. Since receptors for these peptides (AT1aR, SCTR) are coexpressed in osmoregulatory centers, a possible mechanism is formation of a crossclass receptor heterocomplex. Here, we demonstrate such a complex and its functional importance to modulate signaling. Association of AT1aR with SCTR reduced ability of SCT to stimulate cyclic adenosine monophosphate (cAMP), with signaling augmented in presence of ANGII or constitutively active AT1aR. Several transmembrane (TM) peptides of these receptors were able to affect their conformation within complexes, reducing receptor BRET signals. AT1aR TM1 affected only formation and activity of the heterocomplex, without effect on homomers of either receptor, and reduced SCT-stimulated cAMP responses in cells expressing both receptors. This peptide was active in vivo by injection into mouse lateral ventricle, thereby suppressing water-drinking behavior after hyperosmotic shock, similar to SCTR knockouts. This supports the interpretation that active conformation of AT1aR is a key modulator of cAMP responses induced by SCT stimulation of SCTR. The SCTR/AT1aR complex is physiologically important, providing differential signaling to SCT in settings of hyperosmolality or food intake, modulated by differences in levels of ANGII.

Original languageEnglish (US)
Pages (from-to)2632-2644
Number of pages13
JournalFASEB Journal
Volume28
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Secretin
Angiotensins
Peptide Receptors
Cyclic AMP
Peptides
Drinking Behavior
Aptitude
Conformations
Lateral Ventricles
Shock
Eating
Drinking Water
Modulators
Injections
Water
Brain
Cells
secretin receptor

Keywords

  • Angiotensin II
  • In vivo analysis
  • Secretin

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Lee, L. T. O., Ng, S. Y. L., Chu, J. Y. S., Sekar, R., Harikumar, K. G., Miller, L. J., & Chow, B. K. C. (2014). Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex. FASEB Journal, 28(6), 2632-2644. https://doi.org/10.1096/fj.13-246868

Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex. / Lee, Leo T O; Ng, Stephanie Y L; Chu, Jessica Y S; Sekar, Revathi; Harikumar, Kaleeckal G.; Miller, Laurence J; Chow, Billy K C.

In: FASEB Journal, Vol. 28, No. 6, 2014, p. 2632-2644.

Research output: Contribution to journalArticle

Lee, Leo T O ; Ng, Stephanie Y L ; Chu, Jessica Y S ; Sekar, Revathi ; Harikumar, Kaleeckal G. ; Miller, Laurence J ; Chow, Billy K C. / Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex. In: FASEB Journal. 2014 ; Vol. 28, No. 6. pp. 2632-2644.
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