Modulation of the Ca2+-activated K+ current sIAHP by a phosphatase-kinase balance under basal conditions in rat CA1 pyramidal neurons

The slow Ca2+-activated K+ current, sI(AHP), underlying spike frequency adaptation, was recorded with the whole cell patch-clamp technique in CA1 pyramidal neurons in rat hippocampal slices. Inhibitors of serine/threonine protein phosphatases (microcystin, calyculin A, cantharidic acid) caused a gradual decrease of sI(AHP) amplitude, suggesting the presence of a basal phosphorylation-dephosphorylation turnover regulating sI(AHP) Because selective calcineurin (PP-2B) inhibitors did not affect the amplitude of sIAHP, protein phosphatase 1 (PP-1) or 2A (PP-?A) are most likely involved in the basal regulation of this current. The ATP analogue, ATP-gamma-S, caused a gradual decrease in the sI(AHP) amplitude, supporting a role of protein phosphorylation in the basal modulation of sI(AHP) When the protein kinase A (PKA) inhibitor adenosine-3',5'-monophosphorothioate, Rp-isomer (Rp-cAMPS) was coapplied with the phosphatase inhibitor microcystin, it prevented the decrease in the sI(AHP) amplitude that was observed when microcystin alone was applied. Furthermore, inhibition of PKA by Rp-cAMPS led to an increase in the sI(AHP) amplitude. Finally, an adenylyl cyclase inhibitor (SQ22,536) and adenosine 3',5'-cyclic monophosphate-specific type TV phosphodiesterase inhibitors (Ro 20-1724 and rolipram) led to an increase or a decrease in the sI(AHP) amplitude, respectively. These findings suggest that a balance between basally active PKA and a phosphatase (PP-1 or PP-2A) is responsible for the tonic modulation of sI(AHP) resulting in a continuous modulation of excitability and firing properties of hippocampal pyramidal neurons.