Hyaluronan Export through Plasma Membranes Depends on Concurrent K+ Efflux by Kir Channels

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.

Positive side effects of Ca antagonists for osteoarthritic joints—results of an in vivo pilot study

“…We recently discovered that hyaluronan export by MRP5 is dependent on concurrent K + efflux through Kir channels [12]. …”

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

“…However, since the inhibitory concentrations of verapamil that would be effective on the MRP5 transporter can never be reached in the serum using therapeutic and orally administered drug doses, an alternative hypothesis was suggested; the recent discovery that concurrent K + efflux through Ca 2+ activated Kir channels are required for hyaluronan export through MRP5 [52] suggest that blocking VDCC function and subsequent Ca 2+ influx may inhibit K + efflux and, simultaneously, excessive hyaluronan export. This hypothesis has yet to be validated.…”

Fluorescence Resonance Energy Transfer (FRET) and Proximity Ligation Assays Reveal Functionally Relevant Homo- and Heteromeric Complexes among Hyaluronan Synthases HAS1, HAS2, and HAS3

“…Streptococcal HAS itself forms the pore together with phospholipids, (17,22), although this has not been firmly demonstrated for vertebrate HASs. Modulation of multidrug-resistant transporter activity affects hyaluronan synthesis in mammalian cells, and multidrug resistant proteins have been suggested to mediate hyaluronan transport (23). However, the evidence of hyaluronan extrusion through separate transporters has remained circumstantial, and their role has been disputed (24).…”