Non-genomic convergent and divergent signalling of rapid responses to aldosterone and estradiol in mammalian colon

Studies from our laboratory have demonstrated rapid (< 1 min) non-genomic activation of Na+-H+ exchange, K+ recycling, PKC activity and a PKC-dependent Ca2+ entry through L-type Ca2+ channels specifically by mineralocorticoids in distal colon. Aldosterone directly stimulates the activity of the PKCalpha isoform (but not PKCdelta, PKCepsilon and PKCzeta) in a cell-free assay system containing only purified commercially available enzyme, appropriate substrate peptide, co-factors and lipid vesicles. The primary ion transport target of the non-genomic signal transduction cascad sensitive intracellular alkalinisation within 1 min of hormone addition. Intracellular alkalinisation upregulates an ATP-dependent K+ channel, which is involved in K+ recycling to maintain the electrical driving force for Na+ absorption, while inhibiting a Ca2+-dependent K+ channel, which generates the charge balance for Cl- secretion. The non-genomic response to aldosterone in distal colon appears to enhance the capacity for absorption while down-regulating the potential for secretion. We have also demonstrated rapid (< 1 min) non-genomic activation of Na+-H+ exchange, K+ recycling, PKCa activity, and a PKCdelta- and PKA-dependent Ca2+ entry through di-hydropyridine-blockable Ca2+ channels specifically by 17beta-estradiol in distal colon. These rapid effects are female gender specific and are insensitive to inhibitors of the classical estrogen receptor (ER). 17beta-Estradiol directly stimulated the activity of both PKCS and PKCalpha (but not PKCepsilon or PKCzeta) in a cell-free assay system. E2 rapidly inhibited basolateral K-Ca channel activity which would be expected to result in an acute inhibition of Cl- secretion. Physiological concentrations of E2 (0.1-10 nM) reduced both basal and secretagogue-induced Cl- secretion. This anti-secretory effect of E2 is sensitive to PKC inhibition, intracellular Ca2+ chelation, and is female gender specific and insensitive to inhibitors of the classical ER. These observations link rapid non-genomic activation of second messengers with a rapid gender-specific physiological effect in the whole tissue. Aldosterone and E2 differ in their protein kinase signal transduction and both hormones stimulate specific PKC isoforms indicating both common and divergent signalling systems for salt-retaining steroid hormones. The physiological function of non-genomic effects of aldosterone and estradiol is to shift the balance from net secretion to net absorption in a pluripotential epithelium. (C) 2002 Elsevier Science Inc. All rights reserved.