Zhou Yuehan, Bouyer Patrice, Boron Walter F
Dept. of Cellular and Molecular Physiology, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.
Am J Physiol Renal Physiol. 2006 Aug;291(2):F358-67. doi: 10.1152/ajprenal.00520.2005. Epub 2006 May 16.
A previous study demonstrated that proximal tubule cells regulate HCO(3)(-) reabsorption by sensing acute changes in basolateral CO(2) concentration, suggesting that there is some sort of CO(2) sensor at or near the basolateral membrane (Zhou Y, Zhao J, Bouyer P, and Boron WF Proc Natl Acad Sci USA 102: 3875-3880, 2005). Here, we hypothesized that an early element in the CO(2) signal-transduction cascade might be either a receptor tyrosine kinase (RTK) or a receptor-associated (or soluble) tyrosine kinase (sTK). In our experiments, we found, first, that basolateral 17.5 microM genistein, a broad-spectrum tyrosine kinase inhibitor, virtually eliminates the CO(2) sensitivity of HCO(3)(-) absorption rate (J(HCO(3))). Second, we found that neither basolateral 250 nM nor basolateral 2 microM PP2, a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK, reduces the CO(2)-stimulated increase in J(HCO(3)). 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 CO(2) sensitivity. In conclusion, the transduction of the CO(2) 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 CO(2) on J(HCO(3)); 2) a CO(2) receptor activates an sTK, which would then raise J(HCO(3)); 3) a CO(2) receptor transactivates an RTK; and 4) the CO(2) receptor could itself be an RTK.
先前的一项研究表明，近端小管细胞通过感知基底外侧二氧化碳浓度的急性变化来调节HCO(3)(-)重吸收，这表明在基底外侧膜处或其附近存在某种二氧化碳传感器（周Y、赵J、布耶尔P和博龙WF，《美国国家科学院院刊》102: 3875 - 3880，2005）。在此，我们假设二氧化碳信号转导级联反应中的早期元件可能是受体酪氨酸激酶（RTK）或受体相关（或可溶性）酪氨酸激酶（sTK）。在我们的实验中，我们首先发现，基底外侧17.5微摩尔的染料木黄酮，一种广谱酪氨酸激酶抑制剂，实际上消除了HCO(3)(-)吸收率（J(HCO(3))）对二氧化碳的敏感性。其次，我们发现基底外侧250纳摩尔或2微摩尔的PP2，一种对Src家族具有高亲和力的抑制剂，它也抑制Bcr - Abl sTK以及Kit RTK，并不会降低二氧化碳刺激引起的J(HCO(3))增加。第三，我们发现基底外侧35纳摩尔的PD168393，一种对erbB（即表皮生长因子受体）家族中的RTK具有高亲和力的抑制剂，或者基底外侧10纳摩尔的BPIQ - I，它通过与ATP竞争来阻断erbB RTK，都消除了对二氧化碳的敏感性。总之，二氧化碳信号的转导需要酪氨酸激酶的激活，可能是erbB。可能性包括以下几种：1）一种TK仅仅是二氧化碳对J(HCO(3))产生作用所必需的；2）一种二氧化碳受体激活一种sTK，然后sTK会提高J(HCO(3))；3）一种二氧化碳受体反式激活一种RTK；4）二氧化碳受体本身可能就是一种RTK。
