EGF and HB-EGF modulate inward potassium current in human bladder urothelial cells from normal and interstitial cystitis patients.
Interstitial cystitis (IC) is an idiopathic condition characterized by bladder hyperalgesia. Studies have shown cytokine and purinergic signaling abnormalities in cultured bladder urothelial cells (BUC) from IC patients. We performed single-cell electrophysiological studies in both normal and IC BUC. A strongly inward rectifying potassium current with conductance of the Kir2.1 channel was identified in normal BUC. This current was significantly reduced in IC BUC. Kir2.1 protein and mRNA were detected in both IC and normal BUC. Epidermal growth factor (EGF) caused a dose-dependent decrease in the inward potassium current in normal BUC. EGF is secreted in higher amounts by IC BUC and is known to decrease Kir2.1 conductance by phosphorylation of Kir2.1. Genistein, a nonspecific phosphorylation inhibitor, increased the inward potassium current in IC BUC and blocked the effect of EGF on normal BUC. Treatment of IC BUC with heparin-binding epidermal growth factor-like growth factor (HB-EGF), previously shown to be secreted in lower amounts by IC BUC, significantly increased inward potassium current. These data show that the inward potassium current in BUC can be modulated by EGF and HB-EGF. Changes in BUC membrane potassium conductance caused by altered levels of EGF and HB-EGF may therefore play a role in the pathophysiology of IC.
Sun
Yan
Y
Division of Urology, University of Maryland, 22 S. Greene Street, S8D18, Baltimore, MD 21201, USA.
Chen
Mingkui
M
Lowentritt
Benjamin H
BH
Van Zijl
P Sean
PS
Koch
Kristopher R
KR
Keay
Susan
S
Simard
J Marc
JM
Chai
Toby C
TC
D002478:Cells, Cultured; D018856:Cystitis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C489461:Kir2.1 channel; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; D019833:Genistein; D011505:Protein-Tyrosine Kinases