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

• Published in: Steroids 2002-05, Vol.67 (6), p.483-491
• Main Authors: Harvey, Brian J., Doolan, Christina M., Condliffe, Steven B., Renard, Celine, Alzamora, Rodrigo, Urbach, Valerie
• Format: Article
• Language: English
• Subjects: Aldosterone - pharmacology; Animals; Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; Biophysics; Ca 2; Calcium Channels - drug effects; Calcium Channels - metabolism; Cellular Biology; Cl − secretion; Colon - metabolism; Enzyme Activation - drug effects; Epithelium - metabolism; Estradiol - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Human health and pathology; Humans; Immunology; Innate immunity; Intestine. Mesentery; Isoenzymes - metabolism; K + channels; Life Sciences; Male; Mammals; Microbiology and Parasitology; Na +-H + exchange; Pharmaceutical sciences; Pharmacology; Phospholipases A - metabolism; PKA; PKC; Protein Kinase C - metabolism; Protein Kinase C-alpha; Pulmonology and respiratory tract; Rats; Signal Transduction - drug effects; Signal Transduction - physiology; Sodium-Hydrogen Exchangers - drug effects; Sodium-Hydrogen Exchangers - metabolism; Steroids; Subcellular Processes; Tissues and Organs; Vertebrates: digestive system
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(01)00169-6

Studies from our laboratory have demonstrated rapid ( < 1 min) non-genomic activation of Na +-H + exchange, K + recycling, PKC activity and a PKC-dependent Ca 2+ entry through L-type Ca 2+ channels specifically by mineralocorticoids in distal colon. Aldosterone directly stimulates the activity of the PKCα isoform (but not PKCδ, PKCϵ and PKCζ) 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 cascade elicited by aldosterone in epithelia is the Na +-H + exchanger. In isolated colonic crypts, aldosterone produced a PKCα 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 Ca 2+ -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, PKCα activity, and a PKCδ- and PKA-dependent Ca 2+ entry through di-hydropyridine-blockable Ca 2+ channels specifically by 17β-estradiol in distal colon. These rapid effects are female gender specific and are insensitive to inhibitors of the classical estrogen receptor (ER). 17β-Estradiol directly stimulated the activity of both PKCδ and PKCα (but not PKCϵ or PKCζ) 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 Ca 2+ 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-geno