Ion channels underlying the electrical activity of neurons can be regulated by neurotransmitters via two basic mechanisms: ligand binding and covalent modification. Whereas neurotransmitters often act by binding directly to ion channels, the intracellular messenger cyclic AMP is thought usually to act indirectly, by activating protein kinase A, which in turn can phosphorylate channel proteins. Here we show that cyclic AMP, and transmitters acting via cyclic AMP, can act in a protein kinase A-independent manner in the brain. In hippocampal pyramidal cells, cyclic AMP and norepinephrine were found to cause a depolarization by enhancing the hyperpolarization-activated mixed cation current, IQ (also called Ih). This effect persisted even after protein kinase A activity was blocked, thus strongly suggesting a kinase-independent action of cyclic AMP. The modulation of this current by ascending monoaminergic fibers from the brainstem is likely to be a widespread mechanism, participating in the state control of the brain during arousal and attention.Neurotransmitters can regulate neuronal excitability by activating second-messenger pathways leading to covalent modifications of ion-channel proteins. In particular, a number of transmitters exert their effects by activating cyclic AMP (cAMP) production. cAMP activates protein kinase A (PKA), which in turn can phosphorylate ion channels and other target proteins (1-3). In neurons, this enzyme has so far been regarded as the main intracellular receptor for cAMP (1). However, in a few sensory (4) and muscle (5-7) cells, cAMP has also been found to have direct, PKA-independent effects on some ion channels.In CAl hippocampal neurons, cAMP and the monoamine transmitters activating cAMP production-norepinephrine, serotonin, histamine, and dopamine-are all known to increase excitability by suppressing the Ca2+-activated K+ current, IAHP (8-16), which is a current underlying the slow afterhyperpolarization (sAHP) and spike frequency adaptation (17). The suppression of IAHP has previously been shown to be mediated by PKA for each of these monoamine transmitters (10, 16).We now address the question whether cAMP and the transmitters acting via cAMP can also exert kinase-independent effects in these neurons. A possible candidate for such an unconventional cAMP effect is the depolarization of the membrane potential that accompanies the suppression of IAHP in response to cAMP and monoamine transmitters (8,11, 12). We found that the depolarizing action of cAMP and 13-adrenergic agonists was due to an enhancement of the cation current IQ (also called Ih; refs. 18 and 19) and that this effect persisted even when the activation of PKA, and the associated suppression ofIAHP, was blocked. Thus, it seems that cAMP can enhance the excitability of these neurons by modulating ion channels in a PKAindependent manner.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. ...