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Blunted IgE-Mediated Activation of Mast Cells in Mice Lacking the Ca²⁺-Activated K⁺ Channel K_Ca3.1¹

Ekaterina Shumilina^2,*, Rebecca S. Lam^2,3,*, Florian Wölbing, Nicole Matzner^*, Irina M. Zemtsova^*, Malgorzata Sobiesiak^*, Hasan Mahmud^*, Ulrike Sausbier, Tilo Biedermann^4,, Peter Ruth, Matthias Sausbier and Florian Lang^4,*

^* Department of Physiology, University of Tübingen, Tübingen, Germany; Department of Dermatology, University of Tübingen, Tübingen, Germany; and Department of Pharmacology and Toxicology, Pharmaceutical Institute, University of Tübingen, Tübingen, Germany

Mast cell stimulation by Ag is followed by the opening of Ca²⁺-activated K⁺ channels, which participate in the orchestration of mast cell degranulation. The present study has been performed to explore the involvement of the Ca²⁺-activated K⁺ channel K_Ca3.1 in mast cell function. To this end mast cells have been isolated and cultured from the bone marrow (bone marrow-derived mast cells (BMMCs)) of K_Ca3.1 knockout mice (K_Ca3.1^–/–) and their wild-type littermates (K_Ca3.1^+/+). Mast cell number as well as in vitro BMMC growth and CD117, CD34, and FcRI expression were similar in both genotypes, but regulatory cell volume decrease was impaired in K_Ca3.1^–/– BMMCs. Treatment of the cells with Ag, endothelin-1, or the Ca²⁺ ionophore ionomycin was followed by stimulation of Ca²⁺-activated K⁺ channels and cell membrane hyperpolarization in K_Ca3.1^+/+, but not in K_Ca3.1^–/– BMMCs. Upon Ag stimulation, Ca²⁺ entry but not Ca²⁺ release from intracellular stores was markedly impaired in K_Ca3.1^–/– BMMCs. Similarly, Ca²⁺ entry upon endothelin-1 stimulation was significantly reduced in K_Ca3.1^–/– cells. Ag-induced release of β-hexosaminidase, an indicator of mast cell degranulation, was significantly smaller in K_Ca3.1^–/– BMMCs compared with K_Ca3.1^+/+ BMMCs. Moreover, histamine release upon stimulation of BMMCs with endothelin-1 was reduced in K_Ca3.1^–/– cells. The in vivo Ag-induced decline in body temperature revealed that IgE-dependent anaphylaxis was again significantly (by 50%) blunted in K_Ca3.1^–/– mice. In conclusion, K_Ca3.1 is required for Ca²⁺-activated K⁺ channel activity and Ca²⁺-dependent processes such as endothelin-1- or Ag-induced degranulation of mast cells, and may thus play a critical role in anaphylactic reactions.

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 Deutsche Forschungsgemeinschaft Grants BI 696/3-1 (to F.W. and T.B.), SFB 766 (to F.L.), SFB 685 (to T.B.), and BMBF (to F.L.).

² E.S. and R.S.L. contributed equally to this work.

³ Current address: Department of Molecular Neurogenetics, Max Planck Institute of Biophysics, Max-von-Laue Strasse 3, D-60438 Frankfurt am Main, Germany.

⁴ Address correspondence and reprint requests to Dr. Florian Lang, Department of Physiology, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany, E-mail address: florian.lang{at}uni-tuebingen.de or Dr. Tilo Biedermann, Department of Dermatology, University of Tübingen, Liebermeisterstrasse 25, D-72076 Tübingen, Germany, E-mail address: Tilo.Biedermann{at}med.uni-tuebingen.de

⁵ Abbreviations used in this paper: SOC, store-operated Ca²⁺ channel; BMMC, bone marrow-derived mast cell; HSA, human serum albumin; RVD, regulatory cell volume decrease; TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole.

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