High Resolution Imaging of elementary Ca2+ signals in renal arteries

• Applicant: Dr. Johanna Schleifenbaum
• Subject Area: Anatomy and Physiology ; Pharmacology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 270801446

The global basal [Ca2+]i concentration in the cytoplasm of all cells is normally in the range of 100 to 200 nM. It rises to about 300 nM in smooth muscle cells from resistance arteries, causing vasoconstriction. The group of Prof. Mark Nelson has developed new super-resolution imaging technologies in recent years for the detection of local, subcellular Ca2+ signals in resistance arteries and the determination of their function. These signals are able to trigger a sudden increase in cytoplasmic [Ca2+] to 500-5000 nM; they are created by the opening of channels in the endoplasmic reticulum or the plasma membrane. This enabled the group of Prof. Mark Nelson to identify elementary Ca2+ signals for the first time, such as Ca2+ sparks in smooth muscle cells (by opening of a cluster of 8-10 ryanodine receptors), Ca2+ pulsars in endothelial cells (by opening of inositol trisphosphate (IP3) receptors) and Ca2+ sparklets (by opening of a cluster of four TRPV4 channels) in myoendothelial subdomains (myoendothelial projections, MEP) of blood vessels. All these results were obtained in non-renal vessels. In the present research project, elementary Ca2+ signaling pathways in arterial blood vessels of the kidney will be examined for the first time. Novel imaging technologies will be used for this purpose that are developed and will be further developed on the basis of novel biosensors in the laboratory of Prof. Mark Nelson. The project addresses primarily the study of Ca2+ sparklets through TRPV4 channels and novel regulatory mechanisms, in particular whether IP3 serves as a second messenger for the transmission of G-protein-coupled receptor (GPCR) signals from the smooth muscle cells into the endothelial MEPs. For the first time, elementary Ca2+ signals initiated by the opening of TRPV1 channels in the endothelium are to be detected. It will be investigated in situ, in which particular vascular regions of the kidney these signaling pathways occur and what function they provide in the vascular regulation. The selective regulation of TRPV4 or TRPV1 channels may turn out to be a novel promising strategy for the treatment of renovascular hypertension, target organ damage and cardiovascular diseases, eg. sepsis-associated renal vasoconstriction.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Mark T. Nelson