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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Burgoon, Penny W
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University of Rochester
Schools of Dentistry
United States
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Thompson, Jill; Begenisich, Ted (2012) Selectivity filter gating in large-conductance Ca(2+)-activated K+ channels. J Gen Physiol 139:235-44
Almassy, Janos; Begenisich, Ted (2012) The LRRC26 protein selectively alters the efficacy of BK channel activators. Mol Pharmacol 81:21-30
Romanenko, Victor G; Thompson, Jill; Begenisich, Ted (2010) Ca2+-activated K channels in parotid acinar cells: The functional basis for the hyperpolarized activation of BK channels. Channels (Austin) 4:278-88
Taylor, Simon R J; Gonzalez-Begne, Mireya; Sojka, Dorothy K et al. (2009) Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses. J Leukoc Biol 85:978-86
Romanenko, Victor G; Roser, Kurt S; Melvin, James E et al. (2009) The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels. Am J Physiol Cell Physiol 296:C878-88
Thompson, Jill; Begenisich, Ted (2009) Mechanistic details of BK channel inhibition by the intermediate conductance, Ca2+-activated K channel. Channels (Austin) 3:194-204
Nakamoto, Tetsuji; Romanenko, Victor G; Takahashi, Atsushi et al. (2008) Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland. Am J Physiol Cell Physiol 294:C810-9
Romanenko, Victor G; Nakamoto, Tetsuji; Srivastava, Alaka et al. (2007) Regulation of membrane potential and fluid secretion by Ca2+-activated K+ channels in mouse submandibular glands. J Physiol 581:801-17
Nakamoto, Tetsuji; Srivastava, Alaka; Romanenko, Victor G et al. (2007) Functional and molecular characterization of the fluid secretion mechanism in human parotid acinar cells. Am J Physiol Regul Integr Comp Physiol 292:R2380-90
Romanenko, Victor; Nakamoto, Tetsuji; Srivastava, Alaka et al. (2006) Molecular identification and physiological roles of parotid acinar cell maxi-K channels. J Biol Chem 281:27964-72