Approximately 20% of xerostomia cases are of unknown etiology. Many of these idiopathic """"""""dry mouth"""""""" disorders are likely due to genetic defects in the fluid transport mechanism. An initial step in the development of treatments for these latter individuals is to identify the key transport proteins involved in the fluid secretion process. Secretion is driven by the activation of K+ and C1-channels. Several distinct types of K+ and Cl- channels have been functionally identified in salivary acinar cells, but only a few of these have been identified as specific gene products. Some of the properties of these proteins have been determined but little is known about the specific contribution these channels make to the fluid secretion process. Thus, the long-term objective of this Subproject is to identify the K+ and Cl-channel proteins essential for saliva production in human and mouse parotid glands. We will attempt to corroborate our findings in humans identified as suffering from idiopathic dry mouth as part of Subproject 3.
Aim 1 will distinguish which of the different K+ and Cl-channels are functionally important to the production of saliva by characterizing channel different K+ and Cl-channels are functionally important in the production of saliva by characterizing channel biophysics. We will coordinate our efforts with Subproject 1 in order to determine the physiologically relevant effects of agonist-induced signals on the activation of K+ and Cl-channels.
In Aim 2, the molecular identity of the channels expressed in human and mouse parotid acinar cells will be determined by cloning cDNAs that encode the corresponding K+ and Cl- channel proteins. The results from Aims 1 and 2, as well as those from Subproject 1, will provide essential information for predicting the role of individual channels in the secretion process. However, owing to the lack of different pharmacology for many channels in the test of the importance of a given protein can be obtained most easily by studying an animal defective in the expression of the channel.
In Aim 3 the functional significance of specific channel proteins will be determined by examining the effects of gene disruption. Mice lacking expression of two different Cl-channels are currently available for study (CFTR and C1C3). Additional channels found to play critical roles in secretion that can not be selectively blocked with inhibitors will be eliminated in mice by targeted recombination. The results of these studies are expected to uncover the genetic basis for some forms of idiopathic salivary gland hypofunction and to provide a foundation for the development of treatments for these individuals as well as those patients suffering from other forms of salivary gland dysfunction.
| Reyes, Juan Pablo; Perez-Cornejo, Patricia; Hernandez-Carballo, Carmen Y et al. (2008) Na+ modulates anion permeation and block of P2X7 receptors from mouse parotid glands. J Membr Biol 223:73-85 |
| 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 |
| 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 |
| Thompson, Jill; Begenisich, Ted (2006) Membrane-delimited inhibition of maxi-K channel activity by the intermediate conductance Ca2+-activated K channel. J Gen Physiol 127:159-69 |
| Hartzell, Criss; Putzier, Ilva; Arreola, Jorge (2005) Calcium-activated chloride channels. Annu Rev Physiol 67:719-58 |
| Melvin, James E; Yule, David; Shuttleworth, Trevor et al. (2005) Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu Rev Physiol 67:445-69 |
| Tsaneva-Atanasova, K; Yule, D I; Sneyd, J (2005) Calcium oscillations in a triplet of pancreatic acinar cells. Biophys J 88:1535-51 |
| Mignen, Olivier; Thompson, Jill L; Yule, David I et al. (2005) Agonist activation of arachidonate-regulated Ca2+-selective (ARC) channels in murine parotid and pancreatic acinar cells. J Physiol 564:791-801 |
| Brown, David A; Bruce, Jason I E; Straub, Stephen V et al. (2004) cAMP potentiates ATP-evoked calcium signaling in human parotid acinar cells. J Biol Chem 279:39485-94 |
| Perez-Cornejo, Patricia; Arreola, Jorge (2004) Regulation of Ca(2+)-activated chloride channels by cAMP and CFTR in parotid acinar cells. Biochem Biophys Res Commun 316:612-7 |
Showing the most recent 10 out of 33 publications
