BK channels play a counter-adaptive role in drug tolerance and dependence

Ghezzi, Alfredo; Pohl, Jascha B.; Wang, Yan; Atkinson, Nigel S.

doi:10.1073/pnas.1005439107

Cited by 43 publications

(67 citation statements)

References 34 publications

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“…Ethanol increased slowpoke expression in the nervous system coincident with the induction of ethanol tolerance (Cowmeadow et al, 2006). Since an increase of slowpoke expression is also caused by cold, by CO 2 sedation (Ghezzi et al, 2010) or by heat-shock promoters (Cowmeadow et al, 2006) it was suggested that this is a more common mechanism for acquisition of tolerance. Interestingly the Drosophila slowpoke gene appears to contain a binding site for CREB (cyclic-AMP response element binding protein) which has been implicated in learning and memory and hence may also be involved in the ethanol response (Cowmeadow et al, 2006) and possibly in the memory deficits after excessive alcohol intake.…”

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

“…The drugs increased expression of the slo gene, enhanced neuronal excitation by reducing the refractory period between action potentials and augmented seizure susceptibility (Ghezzi et al, 2010). Mutant BK channels exhibiting increased activity were found in humans to cause increased excitability due to rapid repolarization of action potentials (Du et al, 2005).…”

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

See 1 more Smart Citation

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Hermann¹,

Ситдикова²,

Weiger³

2012

Patch Clamp Technique

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Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Hermann¹,

Ситдикова²,

Weiger³

2012

Patch Clamp Technique

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“…The drug induced enhancement of the Ca 2+ -activated K + channel activity causes resistance to sedation by increasing neural excitability. In Drosophila, sedative exposure to alcohols and volatile anesthetics have been shown to inhibit neural excitability, at least in part, by increasing the neuronal refractory period and thus reducing the capacity for repetitive firing (Lin and Nash 1996; Ghezzi et al 2010). Meanwhile, increased slo expression was shown to decrease the neuronal refractory period and enhance repetitive firing, thereby opposing the acute effects of acute drug sedation (Ghezzi et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…In Drosophila, sedative exposure to alcohols and volatile anesthetics have been shown to inhibit neural excitability, at least in part, by increasing the neuronal refractory period and thus reducing the capacity for repetitive firing (Lin and Nash 1996; Ghezzi et al 2010). Meanwhile, increased slo expression was shown to decrease the neuronal refractory period and enhance repetitive firing, thereby opposing the acute effects of acute drug sedation (Ghezzi et al 2010). After drug clearance however, the slo -dependent increase in neural excitability persists and results in an increase in seizure susceptibility—a symptom typical of severe alcohol withdrawal (Ghezzi et al 2010; Ghezzi et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Functional Mapping of the Neuronal Substrates for Drug Tolerance in Drosophila

et al. 2013

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Physical dependence on alcohol and anesthetics stems from neuroadaptive changes that act to counter the effects of sedation in the brain. In Drosophila, exposure to either alcohol or solvent anesthetics have been shown to induce changes in expression of the BK-type Ca2+- activated K+ channel gene slo. An increase in slo expression produces an adaptive modulation of neural activity that generates resistance to sedation and promotes drug tolerance and dependence. Increased BK channel activity counteracts the sedative effects of these drugs by reducing the neuronal refractory period and enhancing the capacity of neurons for repetitive firing. However, the brain regions or neuronal populations capable of producing inducible resistance or tolerance remain unknown. Here we map the neuronal substrates relevant for the slo-dependent modulation of drug sensitivity. Using spatially-controlled induction of slo expression we identify the mushroom bodies, the ellipsoid body and a subset of the circadian clock neurons as pivotal regions for the control of recovery from sedation.

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“…In rodent models, acute ethanol exposure leads to reduced vasopressin, oxytocin and growth hormone release with consequent perturbation in physiology and behavior (7), altered firing rates in nucleus accumbens (8) and dorsal root ganglia neurons (9), and alcohol-induced cerebral artery constriction (10,11). Moreover, studies in both mammals and invertebrate models demonstrate that ethanol targeting of neuronal BK is involved in development of alcohol tolerance and dependence (12)(13)(14)(15)(16). Although the physiological and behavioral consequences of ethanol disruption of BK function have been well documented, it remains unknown whether alcohol modification of BK function results from drug interaction with a defined recognition site(s) in a protein target vs. physical perturbation of the proteolipid environment where the BK protein resides.…”

mentioning

confidence: 99%

An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel

Bukiya

Kuntamallappanavar

Edwards

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Ethanol alters BK (slo1) channel function leading to perturbation of physiology and behavior. Site(s) and mechanism(s) of ethanol-BK channel interaction are unknown. We demonstrate that ethanol docks onto a water-accessible site that is strategically positioned between the slo1 calcium-sensors and gate. Ethanol only accesses this site in presence of calcium, the BK channel's physiological agonist. Within the site, ethanol hydrogen-bonds with K361. Moreover, substitutions that hamper hydrogen bond formation or prevent ethanol from accessing K361 abolish alcohol action without altering basal channel function. Alcohol interacting site dimensions are approximately 10.7 × 8.6 × 7.1 Å, accommodating effective (ethanol-heptanol) but not ineffective (octanol, nonanol) channel activators. This study presents: (i) to our knowledge, the first identification and characterization of an n-alkanol recognition site in a member of the voltage-gated TM6 channel superfamily; (ii) structural insights on ethanol allosteric interactions with ligand-gated ion channels; and (iii) a first step for designing agents that antagonize BK channel-mediated alcohol actions without perturbing basal channel function.is a psychoactive agent that has been overwhelmingly consumed by mankind across cultures and civilizations. Alcohol actions on central nervous system (CNS) physiology and behavior are largely independent of beverage type but due to ethanol itself (1). Ethanol alters cell excitability by modifying function of transmembrane (TM) ion channel proteins, including K + channels. These channels constitute the most heterogeneous and extensive group of ion channels, its members belonging to TM2, TM4, and TM6 protein superfamilies. Within this myriad of proteins, several K + channels have been shown to modify behavior in response to acute exposure to ethanol concentrations that reach the CNS and other excitable tissues during alcohol drinking (2-5). However, with the sole exception of the TM2, G protein-regulated inward rectifier K + (GIRK) channel (6), there is no structural information on ethanol-K + channel protein interacting sites currently available. Voltage/Ca 2+ -gated, large conductance K + channels (BK), which are members of the TM6 voltage-gated ion channel superfamily, constitute major mediators of alcohol actions in excitable tissues. Acute exposure to ethanol levels reached in CNS during alcohol intoxication alters BK-mediated currents and thus, elicits widespread and profound modifications in physiology and behavior. In rodent models, acute ethanol exposure leads to reduced vasopressin, oxytocin and growth hormone release with consequent perturbation in physiology and behavior (7), altered firing rates in nucleus accumbens (8) and dorsal root ganglia neurons (9), and alcohol-induced cerebral artery constriction (10, 11). Moreover, studies in both mammals and invertebrate models demonstrate that ethanol targeting of neuronal BK is involved in development of alcohol tolerance and dependence (12-16). Although the physiological and be...

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BK channels play a counter-adaptive role in drug tolerance and dependence

Cited by 43 publications

References 34 publications

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Functional Mapping of the Neuronal Substrates for Drug Tolerance in Drosophila

An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel

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