Abstract
Hyaluronan is synthesized within the cytoplasm and exported into the extracellular matrix through the cell membrane of fibroblasts by the MRP5 transporter. In order to meet the law of electroneutrality, a cation is required to neutralize the emerging negative hyaluronan charges. As we previously observed an inhibiting of hyaluronan export by inhibitors of K+ channels, hyaluronan export was now analysed by simultaneously measuring membrane potential in the presence of drugs. This was done by both hyaluronan import into inside-out vesicles and by inhibition with antisense siRNA. Hyaluronan export from fibroblast was particularly inhibited by glibenclamide, ropivacain and BaCl2 which all belong to ATP-sensitive inwardly-rectifying Kir channel inhibitors. Import of hyaluronan into vesicles was activated by 150 mM KCl and this activation was abolished by ATP. siRNA for the K+ channels Kir3.4 and Kir6.2 inhibited hyaluronan export. Collectively, these results indicated that hyaluronan export depends on concurrent K+ efflux.
Highlights
Hyaluronan is synthesized at the inner side of cell membranes [1], and is exported by the ABC transporters MRP5 of fibroblasts [2] or CFTR of epithelial cells [3]
Is hyaluronan export linked to membrane potential? A set of K+ blocking drugs was used in a concentration dependent manner to simultaneously analyse the influence on the membrane potential and on hyaluronan export in cultures of human skin fibroblasts
Secondary-active transporter proteins mediate uphill transport of a solute by tapping into the free energy provided by the concentration gradient of a coupled ion that is specific to the transporter protein (e.g., H+, K+, or Na+)
Summary
Hyaluronan is synthesized at the inner side of cell membranes [1], and is exported by the ABC transporters MRP5 of fibroblasts [2] or CFTR of epithelial cells [3]. Hyaluronan molecules which are typically exported have a molecular weight of 46106 Da and a diameter of about 300 nm in the fully expanded state enabling them to displace other macromolecules from their territory [4]. It can be retained by CD44 receptor on the outside of the cell membrane, where it reduces the membrane potential [5] or regulates the cell volume [6]. The most likely cation would be K+, because it is the only cation that extrudes in larger quantities and is tightly regulated by a variety of K+ channels
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