Blockade Of SK Channels Research Articles

SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala

At glutamatergic synapses, calcium influx through NMDA receptors (NMDARs) is required for long-term potentiation (LTP); this is a proposed cellular mechanism underlying memory and learning. Here we show that in lateral amygdala pyramidal neurons, SK channels are also activated by calcium influx through synaptically activated NMDARs, resulting in depression of the synaptic potential. Thus, blockade of SK channels by apamin potentiates fast glutamatergic synaptic potentials. This potentiation is blocked by the NMDAR antagonist AP5 (D(-)-2-amino-5-phosphono-valeric acid) or by buffering cytosolic calcium with BAPTA. Blockade of SK channels greatly enhances LTP of cortical inputs to lateral amygdala pyramidal neurons. These results show that NMDARs and SK channels are colocalized at glutamatergic synapses in the lateral amygdala. Calcium influx through NMDARs activates SK channels and shunts the resultant excitatory postsynaptic potential. These results demonstrate a new role for SK channels as postsynaptic regulators of synaptic efficacy.

Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers

Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca 2+-activated K + channels (SK channels or KCa2 channels). This AHP plays an important role in regulating neuronal activity and agents modulating AHP amplitude could have a potential therapeutic interest. It was previously shown that N-methyl-bicuculline iodide blocks SK channels but its GABA A activity represents a serious drawback. In view of the structural analogy between bicuculline and laudanosine 14, several N-quaternary analogues of the latter were developed. It was shown that N-methyl-laudanosine 15 (NML) and N-ethyl-laudanosine 16 induce a reversible and relatively specific blockade of the apamin sensitive AHP in dopaminergic neurones with mean IC 50s of 15, and 47 μM, respectively. Laudanosine 14, N-butyl- 17 and N-benzyl- 18 derivatives were less potent. In order to find pharmacophore elements, modifications were performed at different positions such as C-1, C-6 and C-7. Intracellular recordings on rat midbrain dopaminergic neurones were made in order to evaluate the putative blockade of SK channels by these molecules. Simplified structures such as tetrahydroisoquinoline derivatives with H or Me at C-1 1– 6 presented no significant activity at 300 μM. The presence of a 1-(3,4-dimethoxybenzyl) moiety seems an important feature. Indeed, compound 8 showed a blockade of the AHP of only 33% at 300 μM while compound 13 blocked it by 67%, respectively, at the same concentration. Binding experiments were also performed. Binding affinities for SK channels are in good agreement with electrophysiological data. These results indicate that the presence of a charged nitrogen group is an essential point for the affinity on SK channels. Finally, because of the similar activity of both enantiomers of NML 19 and 20, the interaction site may present a symmetrical configuration.

Propofol-Block of SK Channels in Reticular Thalamic Neurons Enhances GABAergic Inhibition in Relay Neurons

The GABAergic reticular thalamic nucleus (RTN) is a major source of inhibition for thalamocortical neurons in the ventrobasal complex (VB). Thalamic circuits are thought to be an important anatomic target for general anesthetics. We investigated presynaptic actions of the intravenous anesthetic propofol in RTN neurons, using RTN-retained and RTN-removed brain slices. In RTN-retained slices, focal and bath application of propofol increased intrinsic excitability, temporal summation, and spike firing rate in RTN neurons. Propofol-induced activation was associated with suppression of medium afterhyperpolarization potentials. This activation was mimicked and completely occluded by the small conductance calcium-activated potassium (SK) channel blocker apamin, indicating that propofol could enhance RTN excitability by blocking SK channels. Propofol increased GABAergic transmission at RTN-VB synapses, consistent with excitation of presynaptic RTN neurons. Stimulation of RTN resulted in synaptic inhibition in postsynaptic neurons in VB, and this inhibition was potentiated by propofol in a concentration-dependent manner. Removal of RTN resulted in a dramatic reduction of both spontaneous postsynaptic inhibitory current frequency and propofol-mediated inhibition of VB neurons. Thus the existence and activation of RTN input were essential for propofol to elicit thalamocortical suppression; such suppression resulted from shunting through the postsynaptic GABA(A) receptor-mediated chloride conductance. The results indicate that propofol enhancement of RTN-mediated inhibitory input via blockade of SK channels may play a critical role in "gating" spike firing in thalamocortical relay neurons.

Small Conductance Ca2+-Activated K+ Channels as Targets of CNS Drug Development

In most central neurons, small conductance Ca(2+)-activated K(+) channels (SK channels) contribute to afterhyperpolarizations (AHPs), which control neuronal excitability. The medium AHP has pharmacological properties similar to recombinant SK channels, consistent with the hypothesis that SK channels generate this afterhyperpolarization component. It is still unclear how recombinant SK channels are functionally related to the slow AHP component. Cloned SK channels are heteromeric complexes of SK channel subunits and calmodulin. The channels are activated by Ca(2+) binding to calmodulin that induces conformational changes resulting in channel opening. Channel deactivation is the reverse process brought about by dissociation of Ca(2+) from calmodulin. In the mammalian brain, the three SK channel subunits (SK1-3) display partially overlapping distributions. Most of the higher brain regions such as the neocortex and hippocampus show expression of both genes encoding SK1 and SK2 channels, whereas phylogenetically older brain regions such as the thalamus, basal ganglia, cerebellum, and brainstem show high levels of SK3 gene expression. At present, it is still unclear whether native SK channels are generated as heteromeric or homomeric channels. Peptide toxins such as apamin and scyllatoxin, as well as organic compounds such as quaternary salts of bicuculline, dequalinium, UCL 1684 and UCL 1848 serve as non-specific SK channel blockers. The only known exceptions so far are the scorpion toxin tamapin and the peptide inhibitor Lei-Dab(7), which bind preferentially to SK2. Electrophysiological and behavioral studies indicate that blockade of SK channels by apamin increases excitability, lowers the threshold for the induction of synaptic plasticity, and facilitates hippocampus-dependent memory. The potential value of pharmacological SK channel modulation in various pathological states such as increased epileptiform activity, cognitive impairment, pain, mood disorders and schizophrenia will be discussed.

D-tubocurarine reduces GABA responses in rat substantia nigra dopamine neurons.

SynapseVolume 47, Issue 3 p. 236-239 D-Tubocurarine reduces GABA responses in rat substantia nigra dopamine neurons Luigi Caputi, Luigi Caputi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorC. Peter Bengtson, C. Peter Bengtson IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorEzia Guatteo, Ezia Guatteo IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorGiorgio Bernardi, Giorgio Bernardi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorNicola B. Mercuri, Corresponding Author Nicola B. Mercuri [email protected] IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalyFondazione IRCCS S. Lucia, Experimental Neurology Lab, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this author Luigi Caputi, Luigi Caputi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorC. Peter Bengtson, C. Peter Bengtson IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorEzia Guatteo, Ezia Guatteo IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorGiorgio Bernardi, Giorgio Bernardi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorNicola B. Mercuri, Corresponding Author Nicola B. Mercuri [email protected] IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalyFondazione IRCCS S. Lucia, Experimental Neurology Lab, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this author First published: 09 December 2002 https://doi.org/10.1002/syn.10164Citations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume47, Issue31 March 2003Pages 236-239 RelatedInformation

Regulation of firing response gain by calcium-dependent mechanisms in vestibular nucleus neurons.

Behavioral reflexes can be modified by experience via mechanisms that are largely unknown. Within the circuitry for the vestibuloocular reflex (VOR), neurons in the medial vestibular nucleus (MVN) show adaptive changes in firing rate responses that are correlated with VOR gain (the ratio of evoked eye velocity to input head velocity). Although changes in synaptic strength are typically assumed to underlie gain changes in the VOR, modulation of intrinsic ion channels that dictate firing could also play a role. Little is known, however, about how ion channel function or regulation contributes to firing responses in MVN neurons. This study examined contributions of calcium-dependent currents to firing responses in MVN neurons recorded with whole cell patch electrodes in rodent brain stem slices. Firing responses were remarkably linear over a wide range of firing rates and showed modest spike frequency adaptation. Firing response gain, the ratio of evoked firing rate to input current, was reduced by increasing extracellular calcium and increased either by lowering extracellular calcium or with antagonists to SK- and BK-type calcium-dependent potassium channels and N- and T-type calcium channels. Blockade of SK channels occluded gain increases via N-type calcium channels, while blocking BK channels occluded gain increases via presumed T-type calcium channels, indicating specific coupling of potassium channels and their calcium sources. Selective inhibition of Ca(2+)/calmodulin-dependent kinase II and broad-spectrum inhibition of phosphatases modulated gain via BK-dependent pathways, indicating that firing responses are tightly regulated. Modulation of firing response gain by phosphorylation provides an attractive mechanism for adaptive control of VOR gain.

Group I metabotropic glutamate receptors activate burst firing in rat midbrain dopaminergic neurons

We have investigated the changes in the spontaneous firing pattern induced by DHPG ((S)-3,5-dihydroxyphenylglycine) and NMDA (N-methyl-d-aspartic acid) on rat dopaminergic neurons in substantia nigra pars compacta (SNc) using sharp microelectrode recordings in in vitro conditions. Twenty-five out of 33 cells modified the regular single-pacemaker activity in burst firing when exposed to the Group I metabotropic glutamate receptor (mGluR) agonist DHPG (30 μM) and d-tubocurarine (500 μM) (d-TC), whereas they all fired in bursts during NMDA (20 μM) plus d-TC application. The blockade of SK-channels by d-TC and apamin was essential for the production of both types of bursts. Although the two drugs induced a similar number of action potentials per burst, the DHPG-induced bursts had a lower frequency, a longer duration and a longer plateau period without spikes. In addition, the DHPG-induced bursting had a longer wash-out, could be reduced or blocked by the mGluR 1 selective, non-competitive antagonist CPCCOEt (7-cyclopropan[b]chromen-1a-carboxylic acid ethyl ester) (100 μM) while it was not affected by the mGluR 5 selective antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine (10 μM). These results suggest that both the activation of glutamate metabotropic type 1 and NMDA ionotropic receptors induce burst firing in the dopaminergic cells of the ventral midbrain when the activity of the SK-channels is reduced.