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

• Applicant: Professor Dr. Stefan H. Heinemann
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Anatomy and Physiology ; Biophysics
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392037398

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.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partner: Professor Dr. Shangwei Hou, Ph.D.