Other than the fact that the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel can be activated by cAMP dependent kinase (PKA), little is known about the signal transduction pathways regulating CFTR. Since G-proteins play a principal role in signal transduction regulating several ion channels [4, 5, 9], we sought to test whether G-proteins control CFTR Cl− conductance (CFTR G Cl ) in the native sweat duct (SD). We permeabilized the basolateral membrane with α-toxin so as to manipulate cytosolic nucleotides. We activated G-proteins and monitored CFTR G Cl activity as described earlier [20, 23, 25]. We now show that activating G-proteins with GTP-γ-S (100 μm) also activates CFTR G Cl in the presence of 5 mm ATP alone (without exogenous cAMP). GTP-γ-S increased CFTR G Cl by 44 ± 20 mS/cm2 (mean ±se; n= 7). GDP (10 mm) inhibited G-protein activation of CFTR G Cl even in the presence of GTP-γ-S. The heterotrimeric G-protein activator (AlF4 −) in the cytoplasmic bath activated CFTR G Cl (increased by 51.5 ± 9.4 mS/cm2 in the presence of 5 mm ATP without cAMP, n= 6), the magnitude of which was similar to that induced by GTP-γ-S. Employing immunocytochemical-labeling techniques, we localized Gαs, Gαi, Gαq, and Gβ at the apical membranes of the sweat duct. Further, we showed that the mutant CFTR G Cl in ducts from cystic fibrosis (CF) subjects could be partially activated by G-proteins. The magnitude of mutant CFTR G Cl activation by G-proteins was smaller as compared to non-CF ducts but comparable to that induced by cAMP in CF ducts. We conclude that heterotrimeric G-proteins are present in the apical membrane of the native human sweat duct which may help regulate salt absorption by controlling CFTR G Cl activity.
The Journal of Membrane Biology – Springer Journals
Published: Jan 1, 2001
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