Cellular and molecular mechanism underlying the modulation of neuronal excitability by heme and heme degradation products

血色素血红素在血红蛋白中已被确定为假基；然而，游离血红素（Fe2+-原卟啉IX）及其降解产物，如一氧化碳（CO）、胆红素、胆红素，以及一系列被总结为胆红素氧化产物（box）的进一步分解代谢物的功能才刚刚开始被阐明。在这里，我们专门研究了外伤性脑损伤和出血性中风后发现的游离血红素及其降解产物（HHDPs）过量存在的细胞和分子后果。我们确定的初步结果表明，HHDPs显著改变神经元的电兴奋性，可能导致创伤后癫痫和出血性中风发作。利用在神经生物学、电生理学、功能成像和离子通道生物物理学方面的互补专业知识，以及新的实验工具和化学物质，该合作项目旨在阐明：(1)血红素及其分解产物影响啮齿动物大脑神经元功能的细胞机制；(2)哪些蛋白质是HHDPs的主要靶点；（iii） HHDPs影响离子通道的分子机制（离子通道对于产生电信号至关重要）。在翻译方法中，我们将进一步将在小鼠大脑和体外试验中获得的结果与患者编码hdp依赖性信号蛋白的基因的单核苷酸多态性联系起来。该研究项目将提供血液来源的信使对神经信号的干扰机制，与创伤后神经功能缺陷有重要的相关性。

The blood pigment heme is well established as prosthetic group in hemoproteins; however, the functions of free heme (Fe2+-protoporphyrin IX) and its degradation products, such as carbon monoxide (CO), biliverdin, bilirubin, and an array of further catabolites summarized as bilirubin oxidation products (BOXes) are only beginning to be elucidated. Here we specifically investigate the cellular and molecular consequences of excessive presence of free heme and its degradation products (HHDPs), as found after traumatic brain injury and hemorrhagic strokes. Our firm preliminary results show that HHDPs markedly alter neuronal electrical excitability, potentially contributing to post traumatic epileptic and post hemorrhagic stroke seizures. Exploiting the complementary expertise in neurobiology, electrophysiology, functional imaging, and ion channel biophysics, as well as novel experimental tools and chemicals, this collaborative project aims at the elucidation of the cellular mechanisms (i) by which heme and its breakdown products affect the function of neurons of the rodent brain, (ii) which proteins are the major targets of HHDPs, and (iii) by which molecular mechanisms ion channels - which are of key importance for generating electrical neuronal signals - are affected by HHDPs. In a translational approach, we will furthermore relate the results obtained in the mouse brain and in in-vitro assays with patients´ single nucleotide polymorphisms in genes coding for HHDP-dependent signaling proteins. The research program will provide mechanistic insight into the interference of blood-derived messengers on neuronal signaling with significant relevance for posttraumatic neurological deficits.