The Physiological Roles of K Channels in Fluid Secretion

Summary

Principal Investigator: TED B BEGENISICH
Abstract: Millions of Americans suffer from salivary gland dysfunction. Salivary fluid secretion is necessary for speaking, eating, and for maintaining oral health and the inability to produce adequate salivary fluid secretion results in a variety of conditions that together comprise a major health problem for a significant proportion of the population. Fluid secreting epithelia utilize a complex interplay of ion channels and transport mechanisms. Sustained fluid secretion requires an increase in intracellular calcium produced by sympathetic nerve stimulation of muscarinic receptors on salivary gland acinar cells. This increase in intracellular calcium activates calcium-sensitive potassium (K) and anion channels which, together, drive fluid secretion. Salivary glands contain two types of calcium-activatedK channels named IK1 and maxi-K. The gene encoding the IK1 channel (Kcnn4) has been identified and Kcnmal is a candidate gene for maxi- K. In spite of considerable effort, the specific roles for these two channels in salivary glands remain unknown. Complicating this issue is the preliminary, novel finding that the activation of IK1 channels inhibits maxi-K channel current. The long term goal of this project is to determine the physiological roles for these two types of K channels. Achieving this goal will require confirming the identity of the maxi-K gene and determining the mechanism of the interaction between them. It is hypothesized that these two channels are co-localized in parotid acinar cells with other proteins and interact directly or through a closely-apposed intermediary and may have different calcium and/or muscarinic sensitivities The calcium and muscarinic sensitivities of these two channels will be measured and their mechanism of interaction tested with a combination of patch clamp electrophysiology, optical, biochemical, and molecular biological techniques. The physiological roles of the two channels will be probed with various physiological measurements of mice deficient in the expression of the two K channelgenes.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Molecular identification and physiological roles of parotid acinar cell maxi-K channels
    Victor Romanenko
    Department of Pharmacology and Physiology, University of Rochester Medical Center, New York 14642, USA
    J Biol Chem 281:27964-72. 2006
  2. ncbi Functional and molecular characterization of the fluid secretion mechanism in human parotid acinar cells
    Tetsuji Nakamoto
    The Center for Oral Biology in the Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Am J Physiol Regul Integr Comp Physiol 292:R2380-90. 2007
  3. pmc Regulation of membrane potential and fluid secretion by Ca2+-activated K+ channels in mouse submandibular glands
    Victor G Romanenko
    Center for Oral Biology in the Aab Institute of Biomedical Sciences and Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    J Physiol 581:801-17. 2007
  4. pmc Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland
    Tetsuji Nakamoto
    Center for Oral Biology, Department of Pharmacology and Physiology, Univ of Rochester Medical Center, Box 611, 601 Elmwood Ave, Rochester, NY 14642, USA
    Am J Physiol Cell Physiol 294:C810-9. 2008
  5. pmc The LRRC26 protein selectively alters the efficacy of BK channel activators
    Janos Almassy
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Mol Pharmacol 81:21-30. 2012
  6. pmc Ca2+-activated K channels in parotid acinar cells: The functional basis for the hyperpolarized activation of BK channels
    Victor G Romanenko
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    Channels (Austin) 4:278-88. 2010
  7. pmc Mechanistic details of BK channel inhibition by the intermediate conductance, Ca2+-activated K channel
    Jill Thompson
    Department of Pharmacology and Physiology and the Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA
    Channels (Austin) 3:194-204. 2009
  8. pmc Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses
    Simon R J Taylor
    Division of Medicine, Imperial College, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK
    J Leukoc Biol 85:978-86. 2009
  9. pmc The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels
    Victor G Romanenko
    Dept of Pharmacology, Box 711, Univ of Rochester Medical Center, Rochester, NY 14642, USA
    Am J Physiol Cell Physiol 296:C878-88. 2009
  10. pmc Selectivity filter gating in large-conductance Ca(2+)-activated K+ channels
    Jill Thompson
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    J Gen Physiol 139:235-44. 2012

Scientific Experts

  • TED B BEGENISICH
  • Victor G Romanenko
  • Tetsuji Nakamoto
  • Jill Thompson
  • James E Melvin
  • Alaka Srivastava
  • Janos Almassy
  • Simon R J Taylor
  • Victor Romanenko
  • Charles D Pusey
  • Kurt S Roser
  • Frederick W K Tam
  • Dorothy K Sojka
  • Mireya Gonzalez-Begne
  • Stephen M Harrison
  • Steven A Sheardown
  • James I Elliott
  • Jill C Richardson
  • Atsushi Takahashi
  • Patricia Perez-Cornejo
  • Catherine E Ovitt
  • Jorge Arreola

Detail Information

Publications10

  1. ncbi Molecular identification and physiological roles of parotid acinar cell maxi-K channels
    Victor Romanenko
    Department of Pharmacology and Physiology, University of Rochester Medical Center, New York 14642, USA
    J Biol Chem 281:27964-72. 2006
    ....
  2. ncbi Functional and molecular characterization of the fluid secretion mechanism in human parotid acinar cells
    Tetsuji Nakamoto
    The Center for Oral Biology in the Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Am J Physiol Regul Integr Comp Physiol 292:R2380-90. 2007
    ..Our results demonstrate that the ion transport mechanisms in human parotid glands are equivalent to those in the mouse, confirming that animal models provide valuable systems for testing therapies to prevent salivary gland dysfunction...
  3. pmc Regulation of membrane potential and fluid secretion by Ca2+-activated K+ channels in mouse submandibular glands
    Victor G Romanenko
    Center for Oral Biology in the Aab Institute of Biomedical Sciences and Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    J Physiol 581:801-17. 2007
    ..Finally, we found that the modest hyperpolarization of cells from the double-null mice was maintained by the electrogenic Na(+),K(+)-ATPase...
  4. pmc Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland
    Tetsuji Nakamoto
    Center for Oral Biology, Department of Pharmacology and Physiology, Univ of Rochester Medical Center, Box 611, 601 Elmwood Ave, Rochester, NY 14642, USA
    Am J Physiol Cell Physiol 294:C810-9. 2008
    ..1 potassium channels localized to the apical membranes of striated and excretory duct cells in the mouse submandibular exocrine gland...
  5. pmc The LRRC26 protein selectively alters the efficacy of BK channel activators
    Janos Almassy
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Mol Pharmacol 81:21-30. 2012
    ..Thus, the LRRC26 BK channel accessory protein selectively alters the pharmacology of BK channels...
  6. pmc Ca2+-activated K channels in parotid acinar cells: The functional basis for the hyperpolarized activation of BK channels
    Victor G Romanenko
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    Channels (Austin) 4:278-88. 2010
    ....
  7. pmc Mechanistic details of BK channel inhibition by the intermediate conductance, Ca2+-activated K channel
    Jill Thompson
    Department of Pharmacology and Physiology and the Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA
    Channels (Austin) 3:194-204. 2009
    ..The mediator of this cytoplasmic pore block may be the IK1 N-terminus...
  8. pmc Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses
    Simon R J Taylor
    Division of Medicine, Imperial College, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK
    J Leukoc Biol 85:978-86. 2009
    ..A potential mechanism for this tissue-specific P2X(7) expression in P2X(7)(-/-) animals is discussed, as is the implication that the immune and indeed neuronal functions of P2X(7) may have been underestimated...
  9. pmc The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels
    Victor G Romanenko
    Dept of Pharmacology, Box 711, Univ of Rochester Medical Center, Rochester, NY 14642, USA
    Am J Physiol Cell Physiol 296:C878-88. 2009
    ....
  10. pmc Selectivity filter gating in large-conductance Ca(2+)-activated K+ channels
    Jill Thompson
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    J Gen Physiol 139:235-44. 2012
    ..Our results add significantly to the evidence against a cytoplasmic gate in BK channels and represent a positive test for selectivity filter gating...