Behavioral effects of apamin, a selective inhibitor of the SKCa-channel, in mice and rats

Staay, Franz Josef van der; Fanelli, Richard J.; Blokland, Arjan; Schmidt, Bernard

doi:10.1016/s0149-7634(99)00043-3

Cited by 57 publications

(40 citation statements)

References 34 publications

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“…This indicates that apamin facilitated memory after minimal spatial or nonspatial training. Apamin did not have a significant effect on memory retention in mice after extensive spatial training, consistent with previous reports of the effects of apamin in mice and rats (Ikonen et al, 1998;Ikonen and Riekkinen, 1999;van der Staay et al, 1999).…”

Section: Discussionsupporting

confidence: 92%

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Small Conductance Ca²⁺-Activated K⁺Channels Modulate Synaptic Plasticity and Memory Encoding

Stackman¹,

Hammond²,

Linardatos³

et al. 2002

J. Neurosci.

254

227

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Activity-dependent changes in neuronal excitability and synaptic strength are thought to underlie memory encoding. In hippocampal CA1 neurons, small conductance Ca 2ϩ -activated K ϩ (SK) channels contribute to the afterhyperpolarization, affecting neuronal excitability. In the present study, we examined the effect of apamin-sensitive SK channels on the induction of hippocampal synaptic plasticity in response to a range of stimulation frequencies. In addition, the role of apamin-sensitive SK channels on hippocampal-dependent memory encoding and retention was also tested. The results show that blocking SK channels with apamin increased the excitability of hippocampal neurons and facilitated the induction of synaptic plasticity by shifting the modification threshold to lower frequencies. This facilitation was NMDA receptor (NMDAR) dependent and appeared to be postsynaptic. Mice treated with apamin demonstrated accelerated hippocampal-dependent spatial and nonspatial memory encoding. They required fewer trials to learn the location of a hidden platform in the Morris water maze and less time to encode object memory in an object-recognition task compared with saline-treated mice. Apamin did not influence long-term retention of spatial or nonspatial memory. These data support a role for SK channels in the modulation of hippocampal synaptic plasticity and hippocampal-dependent memory encoding.

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Section: Discussionsupporting

confidence: 92%

“…Moreover, it was proposed recently that there are differences in apamin sensitivity between mice and rats, with rats being relatively insensitive to the cognitive effects of apamin (van der Staay et al, 1999). However, this claim is not substantiated by recent findings.…”

Section: Discussionmentioning

confidence: 86%

Small Conductance Ca²⁺-Activated K⁺Channels Modulate Synaptic Plasticity and Memory Encoding

Stackman¹,

Hammond²,

Linardatos³

et al. 2002

J. Neurosci.

254

227

View full text Add to dashboard Cite

show abstract

“…Despite these promising findings, however, apamin remains a very toxic compound, and all behavioral testing occurs at doses close to or even overlapping with the adverse effects (van der Staay et al, 1999). The reason for the limited therapeutic window may be the high potency and specific SK subtype selectivity of apamin, favoring SK2 over SK3 and SK1 channels.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Gating Modulation of Small Conductance Ca²⁺-Activated K⁺Channels by the Synthetic Compound (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons

Strøbæk¹,

Hougaard²,

Johansen³

et al. 2006

Mol Pharmacol

108

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“…The lack of SK subtype selective blockers combined with this wide distribution means that their roles cannot be well defined. This lack of specificity also means that current available SK blockers have a very narrow therapeutic window, with an overlap of doses required for therapeutic benefit and those producing toxic effects in animal studies (4). SK channels are blocked by the bee venom toxin apamin, which displays weak subtype selectivity.…”

mentioning

confidence: 99%

Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channels

Weatherall

Seutin

Liégeois

et al. 2011

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

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Activation of small-conductance calcium (Ca 2+ )-dependent potassium (K Ca 2) channels (herein called "SK") produces membrane hyperpolarization to regulate membrane excitability. Three subtypes (SK1-3) have been cloned and are distributed throughout the nervous system, smooth muscle, and heart. It is difficult to discern the physiological role of individual channel subtypes as most blockers or enhancers do not discriminate between subtypes. The archetypical blocker apamin displays some selectivity between SK channel subtypes, with SK2 being the most sensitive, followed by SK3 and then SK1. Sensitivity of SK1 is species specific, with the human isoform being blocked by the toxin, whereas the rat is not. Mutation studies have identified residues within the outer pore that suggest apamin blocks by an allosteric mechanism. Apamin also uses a residue within the S3-S4 extracellular loop to produce a high-sensitivity block. We have identified that a 3-amino acid motif within this loop regulates the shape of the channel pore. This motif is required for binding and block by apamin, suggesting that a change in pore shape underlies allosteric block. This motif is absent in rat SK1, explaining why it is insensitive to block by apamin. The overlapping distribution of SK channel subtype expression suggests that native heteromeric channels may be common. We show that the S3-S4 loop of one subunit overlaps the outer pore of the adjacent subunit, with apamin interacting with both regions. This arrangement provides a unique binding site for each combination of SK subunits within a coassembled channel that may be targeted to produce blockers specific for heteromeric SK channels.patch clamp | afterhyperpolarization P harmacological modulation of small-conductance Ca 2+ -activated potassium (SK/K Ca 2) channels has been suggested as a potential target for a number of disorders including dementia, depression, and cardiac arrhythmias. Three subtypes of SK channel have been cloned, with distinct but partially overlapping expression patterns (1-3). A nonpeptidic subtype-specific blocker of SK channels has yet to be developed. The lack of SK subtype selective blockers combined with this wide distribution means that their roles cannot be well defined. This lack of specificity also means that current available SK blockers have a very narrow therapeutic window, with an overlap of doses required for therapeutic benefit and those producing toxic effects in animal studies (4). SK channels are blocked by the bee venom toxin apamin, which displays weak subtype selectivity. The toxin is most potent at SK2 (IC 50 ∼ 70 pM) (5-9) and SK3 (IC 50 ∼ 0.63-6 nM) (7, 9, 10), followed by the human isoform of SK1 (IC 50 ∼ 1-8 nM) (8, 9), whereas the rat isoform of SK1 is apamin insensitive (11,12). Mutation studies have identified a number of residues within the outer pore that affect block by apamin (7,8,13). For example, an outer pore histidine residue has been shown to be critical for both binding and block by the toxin (7). Structural modeling has place...

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Behavioral effects of apamin, a selective inhibitor of the SKCa-channel, in mice and rats

Cited by 57 publications

References 34 publications

Small Conductance Ca²⁺-Activated K⁺Channels Modulate Synaptic Plasticity and Memory Encoding

Small Conductance Ca²⁺-Activated K⁺Channels Modulate Synaptic Plasticity and Memory Encoding

Inhibitory Gating Modulation of Small Conductance Ca²⁺-Activated K⁺Channels by the Synthetic Compound (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons

Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channels

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Behavioral effects of apamin, a selective inhibitor of the SKCa-channel, in mice and rats

Cited by 57 publications

References 34 publications

Small Conductance Ca2+-Activated K+Channels Modulate Synaptic Plasticity and Memory Encoding

Small Conductance Ca2+-Activated K+Channels Modulate Synaptic Plasticity and Memory Encoding

Inhibitory Gating Modulation of Small Conductance Ca2+-Activated K+Channels by the Synthetic Compound (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons

Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channels

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Small Conductance Ca²⁺-Activated K⁺Channels Modulate Synaptic Plasticity and Memory Encoding

Small Conductance Ca²⁺-Activated K⁺Channels Modulate Synaptic Plasticity and Memory Encoding

Inhibitory Gating Modulation of Small Conductance Ca²⁺-Activated K⁺Channels by the Synthetic Compound (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) Reduces Afterhyperpolarizing Current in Hippocampal CA1 Neurons