RAPID COMMUNICATION Modulation of the Ca-Activated K Current sIAHP by a Phosphatase-Kinase Balance Under Basal Conditions in Rat CA1 Pyramidal Neurons

Pedarzani, Paola, Michael Krause, Trude Haug, Johan F. phate (cAMP) and protein kinase A (PKA) in CA1 pyramiStorm, and Walter Stühmer. Modulation of the Ca-activated dal neurons (Blitzer et al. 1994; Madison and Nicoll 1986; K current sIAHP by a phosphatase-kinase balance under basal Pedarzani and Storm 1993, 1995; Torres et al. 1995), conditions in rat CA1 pyramidal neurons. J. Neurophysiol. 79: whereas other kinases have been proposed to mediate the 3252–3256, 1998. The slow Ca-activated K current, sIAHP, suppression of sIAHP by muscarinic and metabotropic glutaunderlying spike frequency adaptation, was recorded with the mate receptor agonists (Abdul-Ghani et al. 1996; Gerber et whole cell patch-clamp technique in CA1 pyramidal neurons in rat al. 1992; Müller et al. 1992; Pedarzani and Storm 1996; Sim hippocampal slices. Inhibitors of serine/ threonine protein phosphaet al. 1992). tases (microcystin, calyculin A, cantharidic acid) caused a gradual One line of evidence supporting the role of protein phosdecrease of sIAHP amplitude, suggesting the presence of a basal phosphorylation-dephosphorylation turnover regulating sIAHP. Bephorylation in the modulation of sIAHP in hippocampal neucause selective calcineurin (PP-2B) inhibitors did not affect the rons was provided by experiments in which protein phosphaamplitude of sIAHP, protein phosphatase 1 (PP-1) or 2A (PP-2A) tases were blocked. This resulted in a gradual suppression are most likely involved in the basal regulation of this current. The of sIAHP, suggesting the presence of an on-going phosphoryATP analogue, ATP-g-S, caused a gradual decrease in the sIAHP lation-dephosphorylation turnover regulating sIAHP in the abamplitude, supporting a role of protein phosphorylation in the basal sence of stimulation by neurotransmitters (Müller et al. modulation of sIAHP. When the protein kinase A (PKA) inhibitor 1992; Pedarzani and Storm 1993). A similar basal modulaadenosine-3*,5*-monophosphorothioate, Rp-isomer (Rp-cAMPS) tion has been proposed to take place for example in Aplysia was coapplied with the phosphatase inhibitor microcystin, it presensory neurons (Ichinose and Byrne 1991) and in frog vented the decrease in the sIAHP amplitude that was observed when heart, where the L-type Ca current and the delayed rectifier microcystin alone was applied. Furthermore, inhibition of PKA by Rp-cAMPS led to an increase in the sIAHP amplitude. Finally, an current IK are modulated by a tonic balance between the adenylyl cyclase inhibitor (SQ22,536) and adenosine 3*,5 *-cyclic basal activity of kinases and phosphatases (Frace and Hartmonophosphate-specific type IV phosphodiesterase inhibitors (Ro zell 1993). 20–1724 and rolipram) led to an increase or a decrease in the In the present study, we sought to investigate the molecusIAHP amplitude, respectively. These findings suggest that a balance lar components involved in the basal modulation of sIAHP, between basally active PKA and a phosphatase (PP-1 or PP-2A) i.e., in the absence of synaptic stimulation or exogenous is responsible for the tonic modulation of sIAHP, resulting in a neurotransmitter application, in hippocampal neurons. continuous modulation of excitability and firing properties of hippocampal pyramidal neurons.