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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016960-03
Application #
7394463
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Shum, Lillian
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$355,799
Indirect Cost
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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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
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