QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.018788v1 69/2/479    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Milasta, S. Articles by Milligan, G. Search for Related Content PubMed PubMed Citation Articles by Milasta, S. Articles by Milligan, G.

Interactions between the Mas-Related Receptors MrgD and MrgE Alter Signalling and Trafficking of MrgD

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (S.M., J.P., S.A., G.M.); and Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (S.T., M.W., P.C., M.F.)

When expressed via an inducible promoter in human embryonic kidney 293 cells, the rat Mas-related gene D (rMrgD) receptor responded to -alanine but not L-alanine by elevating intracellular [Ca²⁺], stimulating phosphorylation of the mitogenactivated protein kinases known as extracellular signal-regulated kinase (ERK) 1 and ERK2 and translocating from the plasma membrane to punctate intracellular vesicles. By contrast, the related rat Mas-related gene E (rMrgE) receptor did not respond to -alanine. Coexpression of rMrgD with rMrgE, which occurs in peripheral nociceptive neurons, allowed coimmunoprecipitation of the two receptors and resulted in the detection of cell surface rMrgD-rMrgE heterodimers via timeresolved fluorescence resonance energy transfer. These interactions increased the potency of -alanine to phosphorylate ERK1 and ERK2 as well as maintaining the capacity of -alanine to elevate intracellular [Ca²⁺], which was reduced in magnitude and slowed in response with increasing times of expression of rMrgD in isolation. Associated with these effects, the presence of rMrgE restricted -alanine-induced internalization of rMrgD. This is the first report of heterodimeric interactions between members of the Mas-related gene (Mrg) receptor family and indicates that interactions between rMrgD and rMrgE modulate the function of rMrgD. Because the Mrg receptors are potential therapeutic targets in pain, these results suggest that efforts to understand the function and regulation of individual Mrg family receptors may require coexpression of relevant pairs.

Address correspondence to: Graeme Milligan, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. E-mail: g.milligan{at}bio.gla.ac.uk

This article has been cited by other articles:

				M. Canals and G. Milligan Constitutive Activity of the Cannabinoid CB1 Receptor Regulates the Function of Co-expressed Mu Opioid Receptors J. Biol. Chem., April 25, 2008; 283(17): 11424 - 11434. [Abstract] [Full Text] [PDF]

				J. R. Lane, B. Powney, A. Wise, S. Rees, and G. Milligan G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 319 - 330. [Abstract] [Full Text] [PDF]

				J. R. Lane, B. Powney, A. Wise, S. Rees, and G. Milligan Protean Agonism at the Dopamine D2 Receptor: (S)-3-(3-Hydroxyphenyl)-N-propylpiperidine Is an Agonist for Activation of Go1 but an Antagonist/Inverse Agonist for Gi1,Gi2, and Gi3 Mol. Pharmacol., May 1, 2007; 71(5): 1349 - 1359. [Abstract] [Full Text] [PDF]

				R. A. Crozier, S. K. Ajit, E. J. Kaftan, and M. H. Pausch MrgD Activation Inhibits KCNQ/M-Currents and Contributes to Enhanced Neuronal Excitability J. Neurosci., April 18, 2007; 27(16): 4492 - 4496. [Abstract] [Full Text] [PDF]

				L. A. Stoddart, A. J. Brown, and G. Milligan Uncovering the Pharmacology of the G Protein-Coupled Receptor GPR40: High Apparent Constitutive Activity in Guanosine 5'-O-(3-[35S]thio)triphosphate Binding Studies Reflects Binding of an Endogenous Agonist Mol. Pharmacol., April 1, 2007; 71(4): 994 - 1005. [Abstract] [Full Text] [PDF]

				J. Ellis, J. D. Pediani, M. Canals, S. Milasta, and G. Milligan Orexin-1 Receptor-Cannabinoid CB1 Receptor Heterodimerization Results in Both Ligand-dependent and -independent Coordinated Alterations of Receptor Localization and Function J. Biol. Chem., December 15, 2006; 281(50): 38812 - 38824. [Abstract] [Full Text] [PDF]

				M. Canals, L. Jenkins, E. Kellett, and G. Milligan Up-regulation of the Angiotensin II Type 1 Receptor by the MAS Proto-oncogene Is Due to Constitutive Activation of Gq/G11 by MAS J. Biol. Chem., June 16, 2006; 281(24): 16757 - 16767. [Abstract] [Full Text] [PDF]