Properties of Ion Channels that Control Secretion

Summary

Principal Investigator: JOHN ENYEART
Affiliation: The Ohio State University
Country: USA
Abstract: The adrenal cortex of mammals is divided into an outer glomerulosa and inner fasciculata that secrete different corticosteroid hormones, including the mineralocorticoid aldosterone and the glucocorticoid cortisol. These hormones function critically in regulating electrolyte, water, and energy balance, and are therefore vital for maintaining blood pressure and plasma glucose within normal limits. Precise control of blood glucose by cortisol is essential because this sugar is the brain's primary energy source. Hypoglycemia rapidly leads to brain damage and death. Aberrant secretion of corticosteroids causes endocrine pathology, including Cushing's and Addison's diseases. At the cellular level, cortisol secretion by adrenal zona fasciculata (AZF) cells is controlled primarily by the pituitary peptide ACTH, while zona glomerulosa (AZG) cells secrete aldosterone in response to the peripheral peptide Angiotensin II (All). Although many of the physiological stimuli and intracellular messengers that regulate secretion of corticosteroids have been identified, the signaling pathways that link these stimuli to secretion are incompletely understood. In particular, the role of electrical activity and specific ion channels in the secretion of corticosteroids has not been clarified. Bovine AZF and AZG cells express several ion channels that determine their electrical properties and the ionic events involved in secretion. The K+ channel bTREK-1 sets the resting potential, is activated by ATP and inhibited by ACTH and All. Thus, TREK-1 channels act pivotally in integrating hormonal and metabolic signals and coupling these to depolarization-dependent calcium (Ca2+) entry and secretion. A specific model has been developed for ACTH- and All-stimulated cortisol and aldosterone secretion that depends on the generation of Ca2+-dependent action potentials. Specifically, the inhibition of bTREK-1 K+ channels by ACTH and All leads to action potentials driven by opposing voltage-gated Ca2+ and K+ currents. Experiments described in this proposal test this hypothesis and identify signaling pathways that control function and expression of adrenocortical ion channels. Specific Aims will be: 1) To demonstrate that All inhibits bTREK-1 K+ channels in bovine AZF and AZG cells by separate Ca2+ - and ATP hydrolysis-dependent signaling pathways, and to identify their molecular mechanisms. To demonstrate that bTREK-1 channels set the resting potential of bovine AZG cells and that inhibition of these channels by All is coupled to depolarization-dependent aldosterone secretion; 2) To demonstrate that ACTH exerts short and long term control over the electrical properties of bovine AZF cells by regulating both the function and expression of AZF cell ion channels and to characterize the molecular mechanisms involved; and 3) To determine whether the ATP sensitivity of native bTREK-1 channels allows them to function as sensors whose activity varies with the plasma glucose concentration and the metabolic state of the AZF cell.
Funding Period: 1995-09-13 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Modulation of native T-type calcium channels by omega-3 fatty acids
    Sanjay J Danthi
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, OH 43210-1239, USA
    Biochem Biophys Res Commun 327:485-93. 2005
  2. ncbi N6-substituted cAMP analogs inhibit bTREK-1 K+ channels and stimulate cortisol secretion by a protein kinase A-independent mechanism
    Haiyan Liu
    Department of Neuroscience, OSU College of Medicine and Public Health, Columbus, OH, USA
    Mol Pharmacol 76:1290-301. 2009
  3. ncbi Curcumin inhibits ACTH- and angiotensin II-stimulated cortisol secretion and Ca(v)3.2 current
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 1239, USA
    J Nat Prod 72:1533-7. 2009
  4. ncbi Metabolites of an Epac-selective cAMP analog induce cortisol synthesis by adrenocortical cells through a cAMP-independent pathway
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, OH, USA
    PLoS ONE 4:e6088. 2009
  5. ncbi ACTH inhibits bTREK-1 K+ channels through multiple cAMP-dependent signaling pathways
    Haiyan Liu
    Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA
    J Gen Physiol 132:279-94. 2008
  6. ncbi Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5196 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210 1239, USA
    Biochem Biophys Res Commun 370:623-8. 2008
  7. ncbi Potent inhibition of native TREK-1 K+ channels by selected dihydropyridine Ca2+ channel antagonists
    Haiyan Liu
    Department of Neuroscience, 5196 Graves Hall, College of Medicine and Public Health, The Ohio State University, 333 W 10th Ave, Columbus, OH 43210 1239, USA
    J Pharmacol Exp Ther 323:39-48. 2007
  8. ncbi Angiotensin II inhibits native bTREK-1 K+ channels through a PLC-, kinase C-, and PIP2-independent pathway requiring ATP hydrolysis
    Haiyan Liu
    Dept of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5196 Graves Hall, Columbus, OH 43210 1239, USA
    Am J Physiol Cell Physiol 293:C682-95. 2007
  9. ncbi Curcumin potently blocks Kv1.4 potassium channels
    Haiyan Liu
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, OH 43210-1239, USA
    Biochem Biophys Res Commun 344:1161-5. 2006
  10. ncbi Angiotensin II inhibits bTREK-1 K+ channels in adrenocortical cells by separate Ca2+- and ATP hydrolysis-dependent mechanisms
    John J Enyeart
    Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 1239, USA
    J Biol Chem 280:30814-28. 2005

Scientific Experts

Detail Information

Publications11

  1. ncbi Modulation of native T-type calcium channels by omega-3 fatty acids
    Sanjay J Danthi
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, OH 43210-1239, USA
    Biochem Biophys Res Commun 327:485-93. 2005
    ..Inhibition of T-type Ca(2+) channels in neurons and cardiac myocytes could contribute significantly to their protective actions...
  2. ncbi N6-substituted cAMP analogs inhibit bTREK-1 K+ channels and stimulate cortisol secretion by a protein kinase A-independent mechanism
    Haiyan Liu
    Department of Neuroscience, OSU College of Medicine and Public Health, Columbus, OH, USA
    Mol Pharmacol 76:1290-301. 2009
    ..Finally, although 6-modified cAMP analogs exhibit high selectivity in activating PKA over Epac, they also may interact with other unidentified proteins expressed by eukaryotic cells...
  3. ncbi Curcumin inhibits ACTH- and angiotensin II-stimulated cortisol secretion and Ca(v)3.2 current
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 1239, USA
    J Nat Prod 72:1533-7. 2009
    ..2 current. These results identify curcumin as an effective inhibitor of ACTH- and AngII-stimulated cortisol secretion. The inhibition of Ca(v)3.2 current by curcumin may contribute to its suppression of secretion...
  4. ncbi Metabolites of an Epac-selective cAMP analog induce cortisol synthesis by adrenocortical cells through a cAMP-independent pathway
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, OH, USA
    PLoS ONE 4:e6088. 2009
    ..The remarkable increases in cortisol synthesis observed in this study appear to be mediated by a novel cAMP-, Epac- and PKA-independent signaling pathway...
  5. ncbi ACTH inhibits bTREK-1 K+ channels through multiple cAMP-dependent signaling pathways
    Haiyan Liu
    Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA
    J Gen Physiol 132:279-94. 2008
    ..The convergent inhibition of bTREK-1 through parallel PKA- and Epac-dependent mechanisms may provide for failsafe membrane depolarization by ACTH...
  6. ncbi Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5196 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210 1239, USA
    Biochem Biophys Res Commun 370:623-8. 2008
    ..Since TREK-1 is widely expressed in a variety of cells, it is likely that some of the biological actions of curcumin, including its therapeutic effects, may be mediated through inhibition of these K(+) channels...
  7. ncbi Potent inhibition of native TREK-1 K+ channels by selected dihydropyridine Ca2+ channel antagonists
    Haiyan Liu
    Department of Neuroscience, 5196 Graves Hall, College of Medicine and Public Health, The Ohio State University, 333 W 10th Ave, Columbus, OH 43210 1239, USA
    J Pharmacol Exp Ther 323:39-48. 2007
    ....
  8. ncbi Angiotensin II inhibits native bTREK-1 K+ channels through a PLC-, kinase C-, and PIP2-independent pathway requiring ATP hydrolysis
    Haiyan Liu
    Dept of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5196 Graves Hall, Columbus, OH 43210 1239, USA
    Am J Physiol Cell Physiol 293:C682-95. 2007
    ..They also indicate that, under physiological conditions, ANG II inhibits bTREK-1 and depolarizes AZF cells by two, novel, independent pathways that diverge proximal to the activation of PLC...
  9. ncbi Curcumin potently blocks Kv1.4 potassium channels
    Haiyan Liu
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, Columbus, OH 43210-1239, USA
    Biochem Biophys Res Commun 344:1161-5. 2006
    ..It remains to be seen whether any of the therapeutic actions of curcumin might originate with its ability to inhibit Kv1.4 or other voltage-gated K+ channel...
  10. ncbi Angiotensin II inhibits bTREK-1 K+ channels in adrenocortical cells by separate Ca2+- and ATP hydrolysis-dependent mechanisms
    John J Enyeart
    Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210 1239, USA
    J Biol Chem 280:30814-28. 2005
    ..The novel Ca2+-dependent pathway is distinctive in its lack of ATP dependence, and is clearly different from the calmodulin kinase-dependent mechanism by which AngII modulates T-type Ca2+ channels in these cells...
  11. ncbi cAMP analogs and their metabolites enhance TREK-1 mRNA and K+ current expression in adrenocortical cells
    Judith A Enyeart
    Department of Neuroscience, The Ohio State University, College of Medicine and Public Health, 5196 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210 1239, USA
    Mol Pharmacol 77:469-82. 2010
    ..These findings raise significant questions regarding the specificity of 8-(4-chlorophenylthio)-cAMP analogs as cAMP mimetics...