Dr. Alexi Alekov
Institut für Neurophysiologie, OE 4230 (I3, Raum 3330)
Tel. +49 511 532-9391
Intracellular vesicles along the endosomal and lysosomal pathway show pronounced acidity when compared to the cell cytoplasm. These low pH values are physiologically relevant and play a role in numerous cellular processes, e.g. receptor endocytosis and recycling, lysosomal degradation, insulin secretion, apoptosis, neurodegeneration, tumor cell growth, proliferation and motility. Here, CIC proteins play an important role in modulating the rate and extend of intravesicular acidification. Funtionally, these proteins mediate secondary active transmembrane transport with variable stoichometry, exchanging anions for protons across biological membranes. The physiological importance of CIC transport is to support the function of ATP-dependent proton pumps, but also to maintain higher anion concentration in intracellular vesicles when compared to the cytoplasm. Genetic defects in mammalian CIC transporters lead to several diseases, associated with impaired vesicular acidification, e.g. Dent's disease (characterized by proteinuria and kidney stones), lysosomal storage disease, neuronal ceroid lipofusinosis, blindness and osteoporosis.
Interestingly, mammalian CIC transporters can operate in two thermodynamically very different modes: a channel and a coupled transporter modes. This is also the origin of the encountered different effective transport stoichiometry. Our group is interested in the physiological importance of this functional switch in respect of the cellular biology. In addition, we investigate the molecular mechanisms underlying the dual properties of these proteins and the modulation of the functional switch by other signaling cascades.
electrophysiology, patch-clamp, two-electrode voltage clamp, noise analysis, capacitance measurements, ion imaging, fluorescent pH measurements, confocal imaging, cellular localization and co-localization of proteins, vesicle motility, mathematical modeling