Fluorescent ligand binding reveals heterogeneous distribution of adrenoceptors and 'cannabinoid-like' receptors in small arteries

C J Daly, R A Ross, J Whyte, C M Henstridge, A J Irving, J C McGrath

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND AND PURPOSE: Pharmacological analysis of synergism or functional antagonism between different receptors commonly assumes that interacting receptors are located in the same cells. We have now investigated the distribution of alpha-adrenoceptors, beta-adrenoceptors and cannabinoid-like (GPR55) receptors in the mouse arteries.

EXPERIMENTAL APPROACH: Fluorescence intensity from vascular tissue incubated with fluorescent ligands (alpha(1)-adrenoceptor ligand, BODIPY-FL-prazosin, QAPB; beta-adrenoceptor ligand, TMR-CGP12177; fluorescent angiotensin II; a novel diarylpyrazole cannabinoid ligand (Tocrifluor 1117, T1117) was measured with confocal microscopy. Small mesenteric and tail arteries of wild-type and alpha(1B/D)-adrenoceptor-KO mice were used.

KEY RESULTS: T1117, a fluorescent form of the cannabinoid CB(1) receptor antagonist AM251, was a ligand for GPR55, with low affinity for CB(1) receptors. In mesenteric arterial smooth muscle cells, alpha(1A)-adrenoceptors were predominantly located in different cells from those with beta-adrenoceptors, angiotensin receptors or cannabinoid-like (GPR55) receptors. Cells with beta-adrenoceptors predominated at arterial branches. Endothelial cells expressed beta-adrenoceptors, alpha-adrenoceptors and cannabinoid-like receptors. Only endothelial alpha-adrenoceptors appeared in clusters. Adventitia was a rich source of G protein-coupled receptors (GPCRs), particularly fibroblasts and nerve tracts, where Schwann cells bound alpha-adrenoceptor, beta-adrenoceptor and CB-receptor ligands, with a mix of separate receptor locations and co-localization.

CONCLUSIONS AND IMPLICATIONS: Within each cell type, each GPCR had a distinctive heterogeneous distribution with limited co-localization, providing a guide to the possibilities for functional synergism, and suggesting a new paradigm for synergism in which interactions may be either between cells or involve converging intracellular signalling processes.

Original languageEnglish
Pages (from-to)787-96
Number of pages10
JournalBritish Journal of Pharmacology
Volume159
Issue number4
DOIs
Publication statusPublished - Feb 2010

Keywords

  • Angiotensin II
  • Animals
  • Boron Compounds
  • Connective Tissue
  • Endothelium, Vascular
  • Fluorescent Dyes
  • Ligands
  • Male
  • Mesenteric Arteries
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Molecular Imaging
  • Molecular Probe Techniques
  • Muscle, Smooth, Vascular
  • Prazosin
  • Propanolamines
  • Pyrazoles
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, beta
  • Receptors, Cannabinoid
  • Tail

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