Our laboratory is focused on the study of renal potassium channels, a diverse group of integral membrane proteins that facilitate the passive (driven by the electrochemical gradient for K) movement of K across the cell membranes. This work has led to the discovery of two novel K channel genes, KCNA10 (Shaker-related, voltage-gated K channel), KCNK1 (a two-pore channel) and to a gain-of-function mutation in the voltage-gated Shaker K channel, KCNA3. KCNA10, the subject of the present proposal, encodes a voltage-gated, cyclic nucleotide regulated, K-selective channel expressed in kidney, heart and blood vessels. Our main goals are to determine its molecular structure and establish its role in kidney. Preliminary studies suggest that KCNA10 is a heteromultimeric complex as evidenced by the identification of three proteins that interact with KCNA10 and modify its kinetic properties and expression level. We propose to investigate the molecular mechanisms underlying these interactions. In addition, we plan to determine the kinetic properties and renal expression of a KCNA10 splice isoform we recently identified. KCNA10 protein was detected at the luminal membrane of rat proximal tubule by immunocytochemistry using a polyclonal antibody generated in rabbit. Western blotting also confirmed KCNA10 protein expression in rat cortical membrane. Based on the foregoing we hypothesize KCNA10 is a heteromultimeric, voltage-gated, apical K channel that modulates proximal tubular membrane potential. We therefore, propose to confirm the expression of KCNA10 at the apical membrane of proximal tubules using patch clamp.A knockout mouse model for KCNA10 will be generated and characterized fully, with particular attention paid to its role on proximal tubular function. These studies should provide important information regarding the molecular structure of KCNA10 and its role in renal solute homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK048105-08
Application #
6483616
Study Section
Special Emphasis Panel (ZRG1-SSS-5 (01))
Program Officer
Ketchum, Christian J
Project Start
1994-04-01
Project End
2006-03-31
Budget Start
2002-04-15
Budget End
2003-03-31
Support Year
8
Fiscal Year
2002
Total Cost
$304,885
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Desir, Gary V (2009) Regulation of blood pressure and cardiovascular function by renalase. Kidney Int 76:366-70
Li, Guoyong; Xu, Jianchao; Wang, Peili et al. (2008) Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation 117:1277-82
Desir, Gary V (2008) Renalase deficiency in chronic kidney disease, and its contribution to hypertension and cardiovascular disease. Curr Opin Nephrol Hypertens 17:181-5
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
Hebert, Steven C; Desir, Gary; Giebisch, Gerhard et al. (2005) Molecular diversity and regulation of renal potassium channels. Physiol Rev 85:319-71
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
Tian, Shulan; Liu, Weimin; Wu, Yanling et al. (2002) Regulation of the voltage-gated K+ channel KCNA10 by KCNA4B, a novel beta-subunit. Am J Physiol Renal Physiol 283:F142-9
Segal, Alan S; Hayslett, John P; Desir, Gary V (2002) On the natriuretic effect of verapamil: inhibition of ENaC and transepithelial sodium transport. Am J Physiol Renal Physiol 283:F765-70

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