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1 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, United States
* To whom correspondence should be addressed. E-mail: walter.boron{at}yale.edu.
A previous study demonstrated that proximal-tubule cells regulate HCO3- reabsorption by sensing acute changes in basolateral [CO2], suggesting that there is some sort of CO2 sensor at or near the basolateral membrane. Here we hypothesized that an early element in the CO2 signal-transduction cascade might be either a receptor tyrosine kinase (RTK) or a receptor-associated (or soluble) tyrosine kinase (sTK). In our experiments, first, we found that basolateral 17.5µM genistein-a broad-spectrum tyrosine-kinase inhibitor-virtually eliminates the CO2 sensitivity of JHCO3. Second, we found that neither basolateral 250 nM nor basolateral 2 µM PP2-a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK-reduces the CO2-stimulated increase in JHCO3. Third, we found that either basolateral 35 nM PD168393-a high-affinity inhibitor of RTKs in the erbB (i.e., EGF receptor) family-or basolateral 10 nM BPIQ-I-which blocks erbB RTKs by competing with ATP-eliminates the CO2 sensitivity. In conclusion, the transduction of the CO2 signal requires activation of a tyrosine kinase, perhaps an erbB. The possibilities include the following: (1) a TK is simply permissive for the effect of CO2 on JHCO3; (2) a CO2 receptor activates an sTK, which would then raise JHCO3; (3) a CO2 receptor transactivates an RTK; and (4) the CO2 receptor could itself be an RTK.
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