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Received July 18, 2003
Revised August 21, 2003
Accepted after revision October 13, 2003
1 University of Basel
* To whom correspondence should be addressed. E-mail: anita.luthi{at}unibas.ch.
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 neurons. Activation of 
-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 downregulation of basal cAMP levels, respectively. In contrast, a transient (
decay
200 s), supralinear upregulation of Ih was observed upon co-application of Iso and Bac that was larger than that observed with Iso alone. This upregulation 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 upregulation, 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 -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.
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