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Regulation of Cl^--HCO₃^- exchangers by cAMP-dependent protein kinase in adult rat hippocampal CA1 neurons

Christopher L. Brett *, Tony Kelly *, Claire Sheldon * and John Church †

The contributions of HCO₃^--dependent, DIDS-sensitive mechanisms to the maintenance of steady-state pH_i, and the regulation of their activities by cAMP-dependent protein kinase (PKA), were investigated in CA1 neurons with the H⁺-sensitive fluorophore, BCECF. The addition of HCO₃^-/CO₂ to neurons with 'low' (pH_i 7.20) and 'high' (pH_i > 7.20) initial pH_i values under Hepes-buffered conditions, increased and decreased steady-state pH_i, respectively. Conversely, under HCO₃^-/CO₂-buffered conditions, DIDS caused pH_i to decrease and increase in neurons with low and high initial pH_i values, respectively. In the presence, but not the absence, of HCO₃^-, the PKA inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPS; 50 µM) evoked DIDS-sensitive increases and decreases in pH_i in neurons with low and high initial pH_i values, respectively. In contrast, in neurons with low initial pH_i values, activation of PKA with the Sp isomer of cAMPS (Sp-cAMPS; 25 µM) elicited increases in pH_i that were smaller in the presence than in the absence of HCO₃^-, whereas in neurons with high initial pH_i values, Sp-cAMPS-evoked rises in pH_i were larger in the presence than in the absence of HCO₃^-; the differences between the effects of Sp-cAMPS on pH_i under the different buffering conditions were attenuated by DIDS. Consistent with the possibility that changes in the activities of HCO₃^--dependent, DIDS-sensitive mechanisms contribute to the steady-state pH_i changes evoked by the PKA modulators, in neurons with initial pH_i values 7.20, Rp-cAMPS concurrently inhibited Na⁺-independent Cl^--HCO₃^- exchange and stimulated Na⁺-dependent Cl^--HCO₃^- exchange; in contrast, Sp-cAMPS concurrently stimulated Na⁺-independent Cl^--HCO₃^- exchange and inhibited Na⁺-dependent Cl^--HCO₃^- exchange. Data from a limited number of neurons with initial pH_i values > 7.20 suggested that the directions of the reciprocal changes in anion exchange activities (inhibition or stimulation) evoked by Rp- and Sp-cAMPS may be opposite in cells with low vs. high resting pH_i values. Taken together, the results indicate that the effects of modulating PKA activity on steady-state pH_i in rat CA1 neurons under HCO₃^-/CO₂-buffered conditions reflect not only changes in Na⁺-H⁺ exchange activity but also changes in Na⁺-dependent and Na⁺-independent Cl^--HCO₃^- exchange activity that, in turn, may be dependent upon the initial pH_i.

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