The slow afterhyperpolarization (sAHP) that follows bursts of action potentials in hippocampal pyramidal neurons is mediated by a Ca²⁺-activated K⁺ current known as sIAHP. This current activates and decays with time constants in the range of seconds. The sIAHP is voltage-independent, and is activated by transient changes in the intracellular Ca²⁺ concentration generated by the opening of voltage-gated Ca²⁺ channels during action potentials. In hippocampal neurons, this current can be easily distinguished from the SK-channel mediated IAHP based on its slower kinetics and pharmacological profile, as the sIAHP is not inhibited by the bee-venom toxin apamin, the prototypical SK channel blocker. The molecular identity of the channels underlying the sIAHP is as yet unknown. The sAHP is responsible for the late phase of spike frequency adaptation and leads to a strong reduction of action potential firing. A trademark feature of sIAHP is its modulation by several neurotransmitters and second messenger pathways. In particular, the mechanism of sIAHP suppression by monoamine transmitters (noradrenaline, dopamine, histamine and serotonin) has been widely studied and involves cAMP as a second messenger and the activation of protein kinase A (PKA). Additionally, in the absence of neurotransmitters, the sIAHP is tonically modulated by the basal level of activity of PKA and a serine/threonine protein phosphatase, suggesting that the sAHP channels might be part of a signaling complex. In the attempt of identifying possible components of such complexes, we have first focused on specific adenylyl cyclases and investigated their role in the modulation of sIAHP by monoamine transmitters and synaptic activity. In particular, we have addressed the role of the calcium-stimulated adenylyl cyclases, AC1 and AC8, by using genetically modified mice. We shall present evidence supporting the specific involvement of AC1/AC8 in the modulation of sIAHP by synaptic activity, while different adenylyl cyclase subtypes mediate the inhibition of the current by monoamine transmitters.

Acknowledgements:

We thank Prof. D. Storm and Dr G. C. Chan (University of Washington, Seattle) for the AC1/AC8 double knock-out mice, and Dr M. Stocker (UCL Neuroscience, Physiology and Pharmacology) for his help with the experiments and valuable discussion. This work was supported by the Medical Research Council.