Many of us will be eventually afflicted with vascular disorders, such as hypertension and brain hemorrhage. Cerebral hemorrhage is often followed by delayed cerebral vasospasm, which itself represents a significant morbidity and mortality factor. Cerebral vasospasm is characterized by a long-lasting abnormal contraction of vascular smooth muscle cells. Previous studies have suggested that blood breakdown products, such as heme, CO, bilirubin and bilirubin oxidation end products (BOXes), may be involved but the underlying mechanism has remained elusive. Among the many proteins involved in regulation of vascular smooth muscles, large-conductance calcium- and voltage-activated (Slo1 BK) potassium channels play a critical role in vascular relaxation. The importance of Slo1 channels in regulation of vascular tone suggests that many disorders of vascular relaxation, including cerebral vasospasm, may involve dysregulation of Slo1 channels. Because bilirubin and bilirubin oxidation end products are implicated in vasospasm and Slo1 channels play a critical role in regulation of vascular tone, we hypothesize that heme catabolic products may contribute to cerebral vasospasm by modulating Slo1 channels. To test this hypothesis, effects of heme catabolic products (CO, bilirubin and bilirubin oxidation end products) on the Slo1 channel function are electrophysiologically and quantitatively investigated using macroscopic and single-channel ionic current and macroscopic gating current measurements. These biophysical measurements are complemented with physiological isometric force measurements using aortic blood vessels from wild-type and Slo1 knockout mice. The results expected from the research program proposed will establish a new paradigm of CO sensing by Slo1 and will highlight Slo1 channels as an important causal link between cerebral hemorrhage and cerebral vasospasm. These novel conceptual frameworks in turn suggest new therapeutic strategies for disorders of vascular relaxation including delayed cerebral vasospasm.
| Tian, Yutao; Aursnes, Marius; Hansen, Trond Vidar et al. (2016) Atomic determinants of BK channel activation by polyunsaturated fatty acids. Proc Natl Acad Sci U S A 113:13905-13910 |
| Han, Bo; He, Kunyan; Cai, Chunlin et al. (2016) Human EAG channels are directly modulated by PIP2 as revealed by electrophysiological and optical interference investigations. Sci Rep 6:23417 |
| Hoshi, T; Heinemann, S H (2016) Modulation of BK Channels by Small Endogenous Molecules and Pharmaceutical Channel Openers. Int Rev Neurobiol 128:193-237 |
| Schink, Martin; Leipold, Enrico; Schirmeyer, Jana et al. (2016) Reactive species modify NaV1.8 channels and affect action potentials in murine dorsal root ganglion neurons. Pflugers Arch 468:99-110 |
| Tian, Yutao; Ullrich, Florian; Xu, Rong et al. (2015) Two distinct effects of PIP2 underlie auxiliary subunit-dependent modulation of Slo1 BK channels. J Gen Physiol 145:331-43 |
| Golder, Francis J; Dax, Scott; Baby, Santhosh M et al. (2015) Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator. Anesthesiology 123:1093-104 |
| Hoshi, Toshinori; Armstrong, Clay M (2015) The Cole-Moore Effect: Still Unexplained? Biophys J 109:1312-6 |
| Sahoo, Nirakar; Hoshi, Toshinori; Heinemann, Stefan H (2014) Oxidative modulation of voltage-gated potassium channels. Antioxid Redox Signal 21:933-52 |
| Ojha, Navin K; Nematian-Ardestani, Ehsan; Neugebauer, Sophie et al. (2014) Sodium channels as gateable non-photonic sensors for membrane-delimited reactive species. Biochim Biophys Acta 1838:1412-9 |
| Heinemann, Stefan H; Hoshi, Toshinori; Westerhausen, Matthias et al. (2014) Carbon monoxide--physiology, detection and controlled release. Chem Commun (Camb) 50:3644-60 |
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