title: Pacemaker channels in mouse thalamocortical neurones are regulated by distinct pathways of cAMP synthesis.
abstract: 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 beta-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 (taudecay, approximately 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 beta-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.
authors.affiliation: Section of Pharmacology and Neurobiology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
authors.forename: Samuel G A
authors.initials: SG
authors.lastname: Frère
authors.forename: Anita
authors.initials: A
authors.lastname: Lüthi
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009434:Neural Pathways; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013788:Thalamus / Q000166:cytology* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D018755:GABA Agonists; D017981:Receptors, Neurotransmitter; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D001418:Baclofen; D007545:Isoproterenol