Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating-Reference-Cited by-同舟云学术

Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating

Published:2022-08-04 Issue:32 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Oyama Kotaro¹²³⁴^ORCID,Zeeb Vadim⁵^ORCID,Yamazawa Toshiko⁶⁷⁸^ORCID,Kurebayashi Nagomi⁹^ORCID,Kobirumaki-Shimozawa Fuyu³^ORCID,Murayama Takashi⁹^ORCID,Oyamada Hideto¹⁰,Noguchi Satoru¹¹^ORCID,Inoue Takayoshi¹²,Inoue Yukiko U.¹²^ORCID,Nishino Ichizo¹¹^ORCID,Harada Yoshie¹³^ORCID,Fukuda Norio³^ORCID,Ishiwata Shin’ichi⁴^ORCID,Suzuki Madoka²¹³^ORCID

Affiliation:

1. Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Takasaki-shi, Gunma 370-1292, Japan

2. PRESTO, Japan Science and Technology Agency, Kawaguchi-shi, Saitama 332-0012, Japan

3. Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan

4. Department of Physics, Faculty of Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan

5. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia

6. Core Research Facilities, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan

7. Department of Molecular Physiology, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan

8. Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

9. Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan

10. Pharmacological Research Center, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan

11. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira-shi, Tokyo 187-8551, Japan

12. Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira-shi, Tokyo 187-8502, Japan

13. Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan

Abstract

Thermoregulation is an important aspect of human homeostasis, and high temperatures pose serious stresses for the body. Malignant hyperthermia (MH) is a life-threatening disorder in which body temperature can rise to a lethal level. Here we employ an optically controlled local heat-pulse method to manipulate the temperature in cells with a precision of less than 1 °C and find that the mutants of ryanodine receptor type 1 (RyR1), a key Ca 2+ release channel underlying MH, are heat hypersensitive compared with the wild type (WT). We show that the local heat pulses induce an intracellular Ca 2+ burst in human embryonic kidney 293 cells overexpressing WT RyR1 and some RyR1 mutants related to MH. Fluorescence Ca 2+ imaging using the endoplasmic reticulum–targeted fluorescent probes demonstrates that the Ca 2+ burst originates from heat-induced Ca 2+ release (HICR) through RyR1-mutant channels because of the channels’ heat hypersensitivity. Furthermore, the variation in the heat hypersensitivity of four RyR1 mutants highlights the complexity of MH. HICR likewise occurs in skeletal muscles of MH model mice. We propose that HICR contributes an additional positive feedback to accelerate thermogenesis in patients with MH.

Funder

MEXT | Japan Society for the Promotion of Science

MEXT | JST | Precursory Research for Embryonic Science and Technology

Japan Agency for Medical Research and Development

Vehicle Racing Commemorative Foundation

Human Frontier Science Program

Russian Advanced Research Foundation

Naito Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary