Functional reduction of SK3-mediated currents precedes AMPA-receptor-mediated excitotoxicity in dopaminergic neurons

Abstract

In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (ISK) in this system and evaluated their role on homeostasis against excitotoxicity. ISK amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of ISK for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two ISK agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, ISK influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

Selective Positive Modulator of Calcium-Activated Potassium Channels Exerts Beneficial Effects in a Mouse Model of Spinocerebellar Ataxia Type 2

“…If NS13001 indeed acted in our experiments by reducing “metabolic burden” on SCA2 PC cells, it is likely that NS13001 and related compounds may offer potential benefit not only for cerebellar ataxias but also for PD and for other neurodegenerative disorders that affect SK2 or SK3-expressing pacemaking neurons. This hypothesis is consistent with recently reported neuroprotective effects of CyPPA in experiments with dopaminergic neuronal cultures (Benitez et al, 2011; Herrik et al, 2012). The data in the current manuscript suggest that NS13001 should exert even more potent protective effect than CyPPA on SNc neurons both in vitro and in vivo .…”

“…From these results we conclude that NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias. We reasoned that NS13001 may also be useful for treatment of other neurodegenerative disorders that affect pacemaking cells expressing SK2/3 channels, such as for example dopaminergic neurons in SNc (Benitez et al, 2011; Chan et al, 2009, 2010; Surmeier, 2007; Surmeier et al, 2010). Evaluation of NS13001 in animal models of ataxia, PD and other neurodegenerative disorders will be required to test these predictions.…”

Evidence for altered circular smooth muscle cell function in lower esophageal sphincter ofW/Wvmutant mice

“…The availability of mice with the kit mutation that lack ICC-IM allowed investigators to explore the role of ICCs in neurotransmission. Early studies reported complete loss of neurotransmission in these mutant mice (3,4,6), suggesting that ICC-IM indeed play a pivotal role in neurotransmission. However, more recent studies have called this conclusion into question (1,10,16,31,37).…”

“…Intracellular Ca 2ϩ changes were obtained by sequential illumination at 340 and 380 nm and expressed as the fluorescence ratio (F R). Both Ca 2ϩ rise and decay times were analyzed as previously described (4,17). Global Ca 2ϩ rise time was measured as the time needed for the rise from 10 to 90% of maximum, fitted with exponential growth.…”

CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate1

“…(Benítez et al, 2011) showed that the non-selective 1-EBIO as well as CyPPA, two chemically very disparate molecules, were able to counteract AMPA neurotoxicity on DA neurons in culture. The protective role of SK channels was further strengthened by showing that both the peptide blocker apamin and the small molecule negative modulator NS8593 accelerated the death of DA neurons.…”