Mg2+ activates the ryanodine receptor type 2 (RyR2) at intermediate Ca2+ concentrations |
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Authors: | Chugun Akihito Sato Osamu Takeshima Hiroshi Ogawa Yasuo |
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Institution: | Department of Pharmacology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. chugun@med.juntendo.ac.jp |
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Abstract: | To clarify whether activity of the ryanodine receptor type 2 (RyR2) is reduced in the sarcoplasmic reticulum (SR) of cardiac muscle, as is the case with the ryanodine receptor type 1 (RyR1), Ca2+-dependent 3H]ryanodine binding, a biochemical measure of Ca2+-induced Ca2+ release (CICR), was determined using SR vesicle fractions isolated from rabbit and rat cardiac muscles. In the absence of an adenine nucleotide or caffeine, the rat SR showed a complicated Ca2+ dependence, instead of the well-documented biphasic dependence of the rabbit SR. In the rat SR, 3H]ryanodine binding initially increased as Ca2+] increased, with a plateau in the range of 10100 µM Ca2+, and thereafter further increased to an apparent peak around 1 mM Ca2+, followed by a decrease. In the presence of these modulators, this complicated dependence prevailed, irrespective of the source. Addition of 0.31 mM Mg2+ unexpectedly increased the binding two- to threefold and enhanced the affinity for 3H]ryanodine at 10100 µM Ca2+, resulting in the well-known biphasic dependence. In other words, the partial suppression of RyR2 is relieved by Mg2+. Ca2+ could be a substitute for Mg2+. Mg2+ also amplifies the responses of RyR2 to inhibitory and stimulatory modulators. This stimulating effect of Mg2+ on RyR2 is entirely new, and is referred to as the third effect, in addition to the well-known dual inhibitory effects. This effect is critical to describe the role of RyR2 in excitation-contraction coupling of cardiac muscle, in view of the intracellular Mg2+ concentration. 3H]ryanodine binding; CICR; stimulation by physiological Mg2+, excitation-contraction coupling in the heart |
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