MODULATION OF THE CA2-ACTIVATED K+ CURRENT SI(AHP) BY A PHOSPHATASE-KINASE BALANCE UNDER BASAL CONDITIONS IN RAT CA1 PYRAMIDAL NEURONS()

The slow Ca2+-activated K+ current, sI(AHP), underlying spike frequenc y adaptation, was recorded with the whole cell patch-clamp technique i n CA1 pyramidal neurons in rat hippocampal slices. Inhibitors of serin e/threonine protein phosphatases (microcystin, calyculin A, cantharidi c acid) caused a gradual decrease of sI(AHP) amplitude, suggesting the presence of a basal phosphorylation-dephosphorylation turnover regula ting 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 adeno sine-3',5'-monophosphorothioate, Rp-isomer (Rp-cAMPS) was coapplied wi th the phosphatase inhibitor microcystin, it prevented the decrease in the sI(AHP) amplitude that was observed when microcystin alone was ap plied. Furthermore, inhibition of PKA by Rp-cAMPS led to an increase i n the sI(AHP) amplitude. Finally, an adenylyl cyclase inhibitor (SQ22, 536) and adenosine 3',5'-cyclic monophosphate-specific type TV phospho diesterase inhibitors (Ro 20-1724 and rolipram) led to an increase or a decrease in the sI(AHP) amplitude, respectively. These findings sugg est 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 h ippocampal pyramidal neurons.