Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, Cork, T12 XF62, Ireland.
J Exp Biol. 2024 Oct 15;227(20). doi: 10.1242/jeb.247640. Epub 2024 Oct 23.
During mammalian cardiomyocyte excitation-contraction coupling, Ca2+ influx through voltage-gated Ca2+ channels triggers Ca2+ release from the sarcoplasmic reticulum (SR) through ryanodine receptor channels. This Ca2+-induced Ca2+ release mechanism controls cardiomyocyte contraction and is exquisitely regulated by SR Ca2+ levels. The histidine-rich calcium-binding protein (HRC) and its aspartic acid-rich paralogue aspolin are high-capacity, low-affinity Ca2+-binding proteins. Aspolin also acts as a trimethylamine N-oxide demethylase. At low intraluminal Ca2+ concentrations, HRC binds to the SR Ca2+-ATPase 2, inhibiting its Ca2+-pumping activity. At high intraluminal Ca2+ levels, HRC interacts with triadin to reduce Ca2+ release through ryanodine receptor channels. This Review analyses the evolution of these Ca2+-regulatory proteins, to gain insights into their roles. It reveals that HRC homologues are present in chordates, annelid worms, molluscs, corals and sea anemones. In contrast, triadin appears to be a chordate innovation. Furthermore, HRC is evolving more rapidly than other cardiac excitation-contraction coupling proteins. This positive selection (or relaxed negative selection) occurs along most of the mammalian HRC protein sequence, with the exception being the C-terminal cysteine-rich region, which is undergoing negative selection. The histidine-rich region of HRC might be involved in pH sensing, as an adaptation to air-breathing, endothermic and terrestrial life. In addition, a cysteine-rich pattern within HRC and aspolin is also found in a wide range of iron-sulfur cluster proteins, suggesting roles in redox reactions and metal binding. The polyaspartic regions of aspolins are likely to underlie their trimethylamine N-oxide demethylase activity, which might be mimicked by the acidic regions of HRCs. These potential roles of HRCs and aspolins await experimental verification.
在哺乳动物心肌细胞兴奋-收缩偶联过程中，电压门控钙通道中的 Ca2+内流通过兰尼碱受体通道触发肌浆网（SR）中的 Ca2+释放。这种 Ca2+诱导的 Ca2+释放机制控制心肌细胞收缩，并受到 SR Ca2+水平的精细调节。富含组氨酸的钙结合蛋白（HRC）及其富含天冬氨酸的同源物 aspolin 是高容量、低亲和力的 Ca2+结合蛋白。Aspolin 还作为三甲基胺 N-氧化物脱甲基酶发挥作用。在低细胞内 Ca2+浓度下，HRC 与 SR Ca2+-ATPase 2 结合，抑制其 Ca2+泵活性。在高细胞内 Ca2+水平下，HRC 与 triadin 相互作用，减少通过兰尼碱受体通道的 Ca2+释放。本综述分析了这些 Ca2+调节蛋白的进化，以深入了解其作用。结果表明，HRC 同源物存在于脊索动物、环节动物、软体动物、珊瑚和海葵中。相比之下，triadin 似乎是脊索动物的创新。此外，HRC 的进化速度比其他心肌兴奋-收缩偶联蛋白更快。这种正选择（或松弛的负选择）发生在大多数哺乳动物 HRC 蛋白序列上，除了富含半胱氨酸的 C 端区域外，该区域正在经历负选择。HRC 的富含组氨酸区域可能参与 pH 感应，作为对空气呼吸、恒温动物和陆地生活的适应。此外，HRC 和 aspolin 中的富含半胱氨酸模式也存在于广泛的铁硫簇蛋白中，提示其在氧化还原反应和金属结合中发挥作用。Aspolins 的多天冬氨酸区域可能是其三甲基胺 N-氧化物脱甲基酶活性的基础，而 HRCs 的酸性区域可能模拟了这种活性。HRCs 和 aspolins 的这些潜在作用有待实验验证。
