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Agonists of the Mas-Related Gene (Mrgs) Orphan Receptors as Novel Mediators of Mast Cell-Sensory Nerve Interactions¹

Min-Goo Lee^2,*,, Xinzhong Dong^2,3,, Qin Liu, Kush N. Patel, Oksoon Hong Choi^*, Becky Vonakis^* and Bradley J. Undem^*

^* Department of Medicine and Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205; and Department of Physiology, Korea University College of Medicine, Seoul, Republic of Korea

IgE-dependent activation of mast cell activation is often associated with symptoms attributed to activation of sensory nerves. Depending on the tissues involved such symptoms include itching, sneezing, irritation, vasodilation, and reflex secretions. In the present study, we hypothesize that sensory neuroactive mediators released from mast cells may include agonists of recently discovered orphan receptors referred to as sensory nerve specific receptors or products of mas related genes. HEK-293 cells expressing MrgC11 receptors and wild-type HEK-293 cells were loaded with the calcium indicator Fura-2. A known stimulant of MrgC11 receptors the RF-amide, neuropeptide FF, evoked a rapid increase in cytosolic calcium in the MrgC11 expressing cells but not in the wild-type HEK-293 cells. IgE-dependent stimulation of either rat basophilic leukemia-2H3 cells (RBL-2H3 cells) or mouse bone marrow-derived mast cells, released a substance(s) that stimulated increases in cytosolic calcium in the MrgC11 expressing cells that far exceeded that seen in control cells. RT-PCR revealed that both mouse mast cells and RBL-2H3 cells express the RF-amide precursor gene proneuropeptide FF (A). Immunohistochemical analysis demonstrated RF-amide immunoreactivity in mouse skin mast cells in situ and in mast cells isolated from mouse skin. These data support the hypothesis that agonists of certain sensory nerve specific receptors or mas related genes may participate in mast cell sensory nerve interactions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research grants to X.D. and B.J.U. from the National Institutes of Health (NS054791-A1 and HL038095).

² M.G.L. and X.D. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Xinzhong Dong, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Wood Basic Science Building Room 906, 725 North Wolfe Street, Baltimore, MD 21205. E-mail address: xdong2{at}jhmi.edu

⁴ Abbreviations used in this paper: GPCR, G protein coupled receptor; Mrg, mas-related gene; SNSR, sensory nerve specific receptor; BMMC, bone-marrow derived mast cell; NPFF, neuropeptide FF; RBL-2H3 cells, rat leukemia-2H3 cell; HSA, human serum albumin.