A Central Role of the BK Potassium Channel in Behavioral Responses to Ethanol in C. elegans

Abstract

The activities of many neuronal proteins are modulated by ethanol, but the fundamental mechanisms underlying behavioral effects of ethanol remain unclear. To identify mechanisms responsible for intoxication, we screened for Caenorhabditis elegans mutants with altered behavioral responses to ethanol. We found that slo-1 mutants, which were previously recognized as having slightly uncoordinated movement, are highly resistant to ethanol in two behavioral assays. Numerous loss-of-function slo-1 alleles emerged from our screens, indicating that slo-1 has a central role in ethanol responses. slo-1 encodes the BK potassium channel. Electrophysiological analysis shows that ethanol activates the channel in vivo, which would inhibit neuronal activity. Moreover, behaviors of slo-1 gain-of-function mutants resemble those of ethanol-intoxicated animals. These results demonstrate that selective activation of BK channels is responsible for acute intoxicating effects of ethanol in C. elegans. BK channel activation may explain a variety of behavioral responses to ethanol in invertebrate and vertebrate systems.

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…In view of the reported specificity of ethanol action within and at differing sites in brain (Bloom and Siggins, 1987;Givens and Breese, 1990a, b;Criswell et al, , 1995Weiner et al, 1997a), additional investigation of the potential regional specificity for each of the mechanisms proposed to collectively influence the in vivo GABAmimetic profile of ethanol should be defined. Given reports that ethanol can affect ion channels that influence membrane potential (see Blednov et al, 2001;Davies et al, 2003;Kobayashi et al, 1999;Lewohl et al, 1999;Carlen et al, 1982;Gruol et al, 1997), this area also warrants further investigation, particularly given that small changes in membrane potential can have potent effects on neural activity (North, 1989). Likewise, further attention should be given to whether GABA uptake is affected by ethanol, as an effect on this function could be a means by which ethanol could influence the effectiveness of GABA released by ethanol.…”

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

“…Many biological phenomena contribute to ethanolinduced responses. These include the involvement of neuropeptide-Y related pathways, [1][2][3][4] glutamate receptors, 5,6 GABA receptors, 7,8 the cAMP signalling pathway, 9,10 the BK potassium channel, SLO-1 [11][12][13] , and membrane perturbation. 14 Many genes and proteins are conserved between Caenorhabditis elegans and humans, including many of those that have been identified as playing a possible role in the effects of ethanol.…”

“…14 Many genes and proteins are conserved between Caenorhabditis elegans and humans, including many of those that have been identified as playing a possible role in the effects of ethanol. 1,13,15 This genetic model therefore potentially provides a powerful new insight into the molecular actions of ethanol through the use of forward genetic screens. A number of previous studies have investigated the behavioural response to ethanol in intact animals.…”

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

“…Most recently, attention has been drawn to the BK channel as a critical player in blood pressure regulation and in the neurotropic effect of ethanol (Davies et al, 2003). Hence, potassium channelmodulating agents have been suggested as therapeutic agents in neurological and cardiovascular disorders (Calderone, 2002).…”