Miotto Marco C, Luna-Figueroa Estefania, Tchagou Carl, Bahlouli Laith, Reiken Steven, Dridi Haikel, Liu Yang, Weninger Gunnar, Marks Andrew R
Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.
Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Medical Center, New York, NY 10032.
Proc Natl Acad Sci U S A. 2025 Jun 17;122(24):e2422082122. doi: 10.1073/pnas.2422082122. Epub 2025 Jun 13.
Ryanodine receptors (RyRs) are intracellular Ca channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.
兰尼碱受体（RyRs）是肌肉收缩所必需的细胞内钙通道。咖啡因是一种黄嘌呤衍生物，几十年来一直已知其可通过增加对钙的敏感性来增强肌肉收缩并提高RyRs的活性。我们之前表明，黄嘌呤是唯一具有生理相关性的黄嘌呤衍生物，它也能结合并激活RyR2。大多数黄嘌呤衍生物和类似物是安全的且被广泛处方，其中最常用的是黄嘌呤氧化还原酶抑制剂别嘌醇（在美国每年约有1500万份处方）。我们提出，增强RyRs活性的黄嘌呤衍生物和类似物可用于先导化合物优化，并最终用于治疗表现出肌肉收缩减少和RyRs活性降低的疾病，如与RyR1相关的疾病、肌肉减少症和心力衰竭。在此，我们通过冷冻电镜显示黄嘌呤衍生物、类似物及其他相关化合物结合至黄嘌呤/咖啡因结合位点并激活RyR1，并确定4-氧代嘧啶是这种相互作用所必需的最小基序。
