Molecular mapping of transmembrane mechanotransduction through the β1 integrin-CD98hc-TRPV4 axis
One of the most rapid (< 4 msec) transmembrane cellular mechanotransduction events involves activation of Transient Receptor Potential Vanilloid 4 (TRPV4) ion channels by mechanical forces transmitted across {beta}1 integrin receptors in endothelial cells, and the transmembrane Solute Carrier family 3 member 2 (CD98hc) protein has been implicated in this response. Here, we show that {beta}1 integrin, CD98hc, and TRPV4 all tightly associate and co-localize in focal adhesions where mechanochemical conversion takes place. CD98hc knock down inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis revealed that forces applied to {beta}1 integrin must be transmitted from its cytoplasmic C-terminus to the CD98hc cytoplasmic tail, and from there to the ankyrin repeat domain of TRPV4 in order to produce ultra-rapid, force-induced, channel activation within the focal adhesion.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC=\"FIGDIR/small/617092v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (44K):\norg.highwire.dtl.DTLVardef@11bfb51org.highwire.dtl.DTLVardef@10bcdaorg.highwire.dtl.DTLVardef@debf89org.highwire.dtl.DTLVardef@1f0bee5_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG SUMMARYA direct path of mechanical signal transfer between {beta}1 integrin, CD98hc, and TRPV4 channels is identified that mediates ultra-rapid transmembrane mechanochemical conversion within focal adhesions.