Premium
Synergistic regulation of CFTR‐bicarbonate conductance by protein kinases and glutamate in the human sweat duct
Author(s) -
Reddy M.M.,
Quinton Paul M
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.934.15
Subject(s) - chemistry , glutamate receptor , kinase , bicarbonate , protein kinase a , conductance , cytosol , biochemistry , endocrinology , enzyme , biology , receptor , mathematics , organic chemistry , combinatorics
CFTR mutations and the resultant loss of both Cl − and HCO 3 − conductances of the CF affected epithelial cells seem responsible for many pathological changes in CF. Previous studies have indicated that the Cl − and HCO 3 − conductance functions of CFTR might be regulated by separate mechanisms (Nature, 423: 756–760, 2003). We further investigated the mechanisms that control CFTR Cl − and HCO 3 − conductances using electrophysiological techniques on α‐toxin permeabilized human sweat duct as previously described (Nature, 423: 756–760, 2003). Our aim was to test the hypothesis that the Cl − and HCO 3 − conductance functions of CFTR are regulated differently by protein kinases (PKA and PKG), glutamate and ATP. We found that the kinase agonists (cAMP and cGMP) and cytosolic glutamate maximally stimulated CFTR Cl − conductance with little synergistic action by these agonists. In contrast, these kinase agonists had little effect on CFTR ‐HCO 3 − conductance (CFTR_gHCO 3 − ) when applied individually. However, simultaneous application of cAMP and cGMP (in the presence of 5 mM ATP) synergistically stimulated CFTR‐gHCO 3 − to 8.0±2.0 ms/cm 2 , n=number of ducts=5). Addition of glutamate or its metabolite, α‐ketoglutarate further enhanced CFTR‐gHCO 3 − to 18.0± 4.0 mS/cm 2 , n=5. These preliminary data appears to suggest that the Cl − and HCO 3 − conductance functions of CFTR required distinct conditions for activation and regulation. Supported by NIH‐RO1 DE14352, NIH‐RO1HL08042, USPHS R01 DK 51889 and the Nancy Olmsted Trust