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Section of Pharmacology and Neurobiology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland
A crucial aspect of pacemaker current (Ih) function is the regulation by cyclic nucleotides. To assess the endogenous mechanisms controlling cAMP levels in the vicinity of pacemaker channels, Ih regulation by G-protein-coupled neurotransmitter receptors was studied in mouse thalamocortical neurones. Activation of ß-adrenergic receptors with (-)-isoproterenol (Iso) led to a small steady enhancement of Ih amplitude, whereas activation of GABAB receptors with (±)-Baclofen (Bac) reduced Ih, consistent with an up- and down-regulation of basal cAMP levels, respectively. In contrast, a transient (
decay, 
200 s), supralinear up-regulation of Ih was observed upon coapplication of Iso and Bac that was larger than that observed with Iso alone. This up-regulation appeared to involve a cAMP synthesis pathway distinct from that recruited by Iso, as it was associated with a reversible acceleration in Ih activation kinetics and an occlusion of modulation by photolytically released cAMP, yet showed an 11 mV as opposed to a 6 mV positive shift in the activation curve and an at least seven-fold increase in duration. GABA, in the presence of the GABAA antagonist picrotoxin, mimicked, whereas N-ethylmaleimide, an inhibitor of Gi-proteins, blocked the up-regulation, supporting a requirement for GABAB receptor activation in the potentiation. Activation of synaptic GABAB responses via stimulation of inhibitory afferents from the nucleus reticularis potentiated Iso-induced increments in Ih, suggesting that synaptically located receptors couple positively to cAMP synthesis induced by ß-adrenergic receptors. These findings indicate that distinct pathways of cAMP synthesis target the pacemaker current and the recruitment of these may be controlled by GABAergic activity within thalamic networks.
(Received 18 July 2003;
accepted after revision 13 October 2003;
first published online 17 October 2003)
Corresponding author A. Lüthi: Department of Pharmacology and Neurobiology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland. Email: anita.luthi{at}unibas.ch
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