Pacemaker channels in mouse thalamocortical neurones are regulated by distinct pathways of cAMP synthesis

A crucial aspect of pacemaker current (I-h) function is the regulation by cyclic nucleotides. To assess the endogenous mechanisms controlling cAMP levels in the vicinity of pacemaker channels, I-h 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 I-h amplitude, whereas activation of GABA(B) receptors with (+/-)-Baclofen (Bac) reduced I-h, consistent with an up- and down-regulation of basal cAMP levels, respectively. In contrast, a transient (tau(decay), similar to200 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 I-h 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 GABA(A) antagonist picrotoxin, mimicked, whereas N-ethylmaleimide, an inhibitor of G(i)-proteins, blocked the up-regulation, supporting a requirement for GABA(B) receptor activation in the potentiation. Activation of synaptic GABA(B) responses via stimulation of inhibitory afferents from the nucleus reticularis potentiated Iso-induced increments in I-h, 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.