A long held concept is that glucocorticoids have no effect on cation transport other than that produced by crossover binding of pharmacologic doses to the aldosterone receptor. However, recent findings have demonstrated that: 1) glucocorticoids not aldosterone maintain basal levels of sodium absorption in colon; 2) glucocorticoid effector is not mediated by binding to the aldosterone receptor and 3) glucocorticoid effector pathways are distinct from those modulated by aldosterone. Aldosterone modulates active electrogenic sodium absorption via the amiloride sensitive sodium pathway of high resistance epithelia while glucocorticoids stimulate active sodium absorption via amiloride insensitive electrogenic pathways without alteration of tissue conductance. Furthermore, it appears that glucocorticoid mediated sodium absorption may be modulated via glucocorticoid receptor IB, a receptor thus far found only in kidney and colon, tissues with glucocorticoid inducible sodium transport. This receptor is clearly distinct from the receptor modulating metabolic events. This proposal focuses on defining the dynamics of receptor IB interaction with hormone and on clarifying the pathway and mechanisms by which glucocorticoids effect cation transport. The glucocorticoid receptor's localization in transporting epithelia will be examined. Post receptor binding events of the glucocorticoid-receptor IB complex will be examined by standard biochemical techniques to determine if receptor IB produces its effect via classic receptor pathways. The aldosterone receptor will be further defined and localized and its post binding kinetics compared with that of the glucocorticoid receptor. The time-course and dose requirements for steroids to alter the transport characteristics of isolated colonic epithelia will be studied in Ussing chambers and correlated with receptor activity. Pharmacologic probes (Amiloride, amphotericin B) coupled with physiologic measurements of transport in vitro using Ussing chambers will test whether GC primarily stimulate luminal membrane processes or basolateral membrane processes to transport cations. Factors known to alter Na conductive channels, NaCl co-transport and the Na-H antiport system will be used to define the effect of steroids on these pathways. Since the colon shares properties in common with all polar epithelia and it now appears that glucocorticoids mediate sodium absorption in several of these tissues, the concepts of glucocorticoid receptor mediated pathways derived from this study should have broad application to other target epithelia.
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| Bastl, C P; Schulman, G; Cragoe Jr, E J (1989) Low-dose glucocorticoids stimulate electroneutral NaCl absorption in rat colon. Am J Physiol 257:F1027-38 |
