Generation and Characterization of Mutant Mice Lacking Ryanodine Receptor Type 3

doi:10.1074/jbc.271.33.19649

Generation and Characterization of Mutant Mice Lacking Ryanodine Receptor Type 3*

From the ^‡ Department of Pharmacology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan,
^§ Department of Pharmacology, Saitama Medical School, Moroyama-machi, Saitama 350-01, Japan,
^∥ Department of Neurochemistry, Tokyo Institute of Psychiatry, Setagaya-ku, Tokyo 156, Japan,
** Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan,
^‡‡ Division of Immunological Diseases, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113, Japan, and
^§§ Department of Cell Biology, Cancer Institute, Toshima-ku, Tokyo 170, Japan

^¶To whom correspondence and reprint requests should be addressed:
Dept. of Pharmacology, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan.
Tel.: 81-3-3812-2111 (ext. 3422); Fax: 81-3-3815-9360; E-mail: takeshim{at}m.u.tokyo.ac.jp.

Abstract

The ryanodine receptor type 3 (RyR-3) functions as a Ca²⁺-induced Ca²⁺ release (CICR) channel and is distributed in a wide variety of cell types including skeletal muscle and smooth muscle cells, neurons, and certain non-excitable cells. However, the physiological roles of RyR-3 are totally unclear. To gain an insight into the function of RyR-3 in vivo, we have generated mice lacking RyR-3 by means of the gene targeting technique. The mutant mice thus obtained showed apparently normal growth and reproduction. Although Ca²⁺-induced Ca²⁺ release from intracellular Ca²⁺ stores of the mutant skeletal muscle differed in Ca²⁺ sensitivity from that of wild-type muscle, excitation-contraction coupling of the mutant muscle seemed to be normal. Moreover, we could not find any significant disturbance in the smooth muscle and lymphocytes from the mutant mice. On the other hand, the mutant mice showed increased locomotor activity, which was about 2-fold greater than that of the control mice. These results indicate that the loss of RyR-3 causes no gross abnormalities and suggest that the lack of RyR-3-mediated Ca²⁺ signaling results in abnormalities of certain neurons in the central nervous system.

Footnotes

↵* This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, Mitsubishi Foundation, Uehara Memorial Foundation, Japan Heart Foundation, and Naito Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) D84236[GenBank] and D84237[GenBank].
↵¹ The abbreviations used are:

RyR

ryanodine receptor

CICR

Ca²⁺-induced Ca²⁺ release

SR

sarcoplasmic reticulum

E-C

excitation-contraction

ES

embryonic stem

PIPES

1,4-piperazinediethanesulfonic acid

MS

methanesulfonate

PSS

physiological salt solution.
- Received June 11, 1996.