Mg2+ activates the ryanodine receptor type 2 (RyR2) at intermediate Ca2+ concentrations.
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), Ca(2+)-dependent [(3)H]ryanodine binding, a biochemical measure of Ca(2+)-induced Ca(2+) 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 Ca(2+) dependence, instead of the well-documented biphasic dependence of the rabbit SR. In the rat SR, [(3)H]ryanodine binding initially increased as [Ca(2+)] increased, with a plateau in the range of 10-100 microM Ca(2+), and thereafter further increased to an apparent peak around 1 mM Ca(2+), followed by a decrease. In the presence of these modulators, this complicated dependence prevailed, irrespective of the source. Addition of 0.3-1 mM Mg(2+) unexpectedly increased the binding two- to threefold and enhanced the affinity for [(3)H]ryanodine at 10-100 microM Ca(2+), resulting in the well-known biphasic dependence. In other words, the partial suppression of RyR2 is relieved by Mg(2+). Ca(2+) could be a substitute for Mg(2+). Mg(2+) also amplifies the responses of RyR2 to inhibitory and stimulatory modulators. This stimulating effect of Mg(2+) 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 Mg(2+) concentration.
Chugun
Akihito
A
Department of Pharmacology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. chugun@med.juntendo.ac.jp
Sato
Osamu
O
Takeshima
Hiroshi
H
Ogawa
Yasuo
Y
D000227:Adenine Nucleotides / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006352:Heart Ventricles; D006801:Humans; D008274:Magnesium / Q000494:pharmacology*; D009994:Osmolar Concentration; D010210:Papillary Muscles / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*
D000227:Adenine Nucleotides; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002110:Caffeine; D008274:Magnesium; D002118:Calcium