application) Disturbances of potassium homeostasis can result in fatal consequences such as cardiac arrest. The kidney is a vital organ that maintains serum potassium concentration in a very narrow range. To achieve this, renal epithelial cells are equipped with membrane transporters such as Na-ATPase and K channels. The exact mechanism of K absorption and secretion in the kidney is not completely understood, however, recent progress suggests that potassium channels may play an important role in the process. In addition to inward rectifier K channels, voltage-gated K channels are also expressed in kidney. Dr. Gary Desir's laboratory has identified several such channels. Two of these have been extensively characterized: Kv1.3 and KCNA10. Although the precise physiological role of these channels in renal K homeostasis is unclear, it is postulated that Kv1.3, in conjunction with ATP-sensitive KATP channels, mediates K exit into interstitium where K can be returned to blood stream or accumulated and recycled back into the cell by Na+,K+-ATPase pump. KCNA10 may participate in K transport, the regulation of vascular tone, the cardiac action potential, and cortisol secretion. To test these hypotheses, I will examine the sub-cellular localization of Kv1.3 in the renal epithelia, and study the Kv1.3 function in vivo using gene-targeting.
The Specific Aims of the project are: (1) Localization of Kv1.3 in renal epithelial cells. (2) Generation of Kv1.3-deficient mice. (3) Characterization of the K0.3-deficient mice. (4) Generation of KCNA10 knockout mouse and Kv1.3/KCNA10 double knockout mouse.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002917-04
Application #
6703060
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2001-04-15
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$131,895
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Li, Yanyan; Wang, Peili; Xu, Jianchao et al. (2007) Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII. Biochem Biophys Res Commun 362:658-64
Li, Yanyan; Wang, Peili; Xu, Jianchao et al. (2006) Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism. Am J Physiol Cell Physiol 290:C345-51
Xu, Jianchao; Li, Guoyong; Wang, Peili et al. (2005) Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest 115:1275-80
Xu, Jianchao; Wang, Peili; Li, Yanyan et al. (2004) The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proc Natl Acad Sci U S A 101:3112-7