Effect of apamin, a toxin that inhibits Ca2+-dependent K+ channels, on learning and memory processes

Messier, Claude; Mourre, Christiane; Bontempi, Bruno; Sif, J.; Lazdunski, Michel; Destrade, Claude

doi:10.1016/0006-8993(91)90950-z

Cited by 114 publications

(60 citation statements)

References 17 publications

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“…Furthermore, there is evidence that application of apamin in vivo improves learning and memory retention in rats (40,41). Taken together with our results, these findings open a number of questions on the possible role of apamin-sensitive SK channels in modulating the integration of synaptic signals in hippocampal pyramidal neurons.…”

Section: Resultssupporting

confidence: 81%

An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

Stocker

Krause

Pedarzani

1999

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

360

435

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In hippocampal and other cortical neurons, action potentials are followed by afterhyperpolarizations (AHPs) generated by the activation of small-conductance Ca 2؉ -activated K ؉ channels (SK channels). By shaping the neuronal firing pattern, these AHPs contribute to the regulation of excitability and to the encoding function of neurons. Here we report that CA1 pyramidal neurons express an AHP current that is suppressed by apamin and is involved in the control of repetitive firing. This current presents distinct kinetic and pharmacological features, and it is modulated differently than the apamin-insensitive slow AHP current. Furthermore, our in situ hybridizations show that the apaminsensitive SK subunits are expressed in CA1 pyramidal neurons, providing a potential molecular correlate to the apaminsensitive AHP current. Altogether, these results clarify the discrepancy between the reported high density of apaminbinding sites in the CA1 region and the apparent lack of an apamin-sensitive current in CA1 pyramidal neurons, and they may explain the effects of this toxin on hippocampal synaptic plasticity and learning.In many neurons of the central nervous system, action potentials are followed by a rise in intracellular Ca 2ϩ leading to a prolonged afterhyperpolarization (AHP) of the membrane (1-4). The currents underlying the AHP are mediated by small-conductance voltage-insensitive Ca 2ϩ -activated K ϩ channels (SK channels), and they can be classified into two groups on the basis of their kinetic and pharmacological properties (5): (i) I AHP is sensitive to the bee venom toxin apamin and presents a relatively fast activation and decay (6); (ii) sI AHP (where s stands for slow) is apamin insensitive, rises to peak and decays with time constants of several hundreds of milliseconds, and is modulated by many neurotransmitters (1, 4). Functionally, activation of I AHP controls the firing frequency in tonically spiking neurons, whereas activation of sI AHP leads to spike frequency adaptation (5). While most excitable cells present an apamin-sensitive I AHP , only a few nerve cells exhibit an apamin-insensitive sI AHP , or both types of currents (4, 5). In the hippocampus, electrophysiological experiments have so far shown a peculiar segregation of AHP currents in different types of neurons, with pyramidal neurons presenting exclusively sI AHP (1, 7), and oriens-alveus interneurons only I AHP (8). These results are in contrast with studies on the distribution of apamin-binding sites in rat brain sections, which show the highest density in the hippocampal CA1 region (9, 10).Three members of the SK family of K ϩ channels have recently been cloned (11). All of them are voltage-insensitive and activated by submicromolar intracellular Ca 2ϩ . Two of them, SK2 and SK3, are blocked by apamin, whereas SK1 is apamin insensitive (11). Given these features, the SK channel subunits cloned so far are likely to participate in the formation of native SK channels, giving rise to apamin-sensitive and -insensitive AHP currents i...

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Section: Resultssupporting

confidence: 81%

An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

Stocker

Krause

Pedarzani

1999

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

360

435

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“…similarities to apamin in brain has been reported (45), and apamin application has profound physiological effects, presumably through its interactions with SK channels. Therefore, understanding the molecular determinants of apamin binding may provide a framework for the design of novel therapeutic agents affecting seizures (15), circadian cycle (16), learning disorders (17), intestinal motility (19), and myotonic dystrophy (23).…”

Section: Discussionmentioning

confidence: 99%

“…2 Intracerebroventricular injections of apamin disturbed the circadian cycle and disrupted normal sleep patterns (16). Rats injected with apamin prior to but not following training showed accelerated acquisition rates and retention times of learned tasks (17), and increased levels of c-fos and c-jun mRNAs in the hippocampus (18). In the periphery, apamin application to guinea pig proximal colon blocked neurotensin-induced relaxation and resulted instead in contraction (19).…”

mentioning

confidence: 99%

Determinants of Apamin and d-Tubocurarine Block in SK Potassium Channels

Ishii¹,

Maylie²,

Adelman³

1997

Journal of Biological Chemistry

245

235

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Small conductance calcium-activated potassium channels show a distinct pharmacology. Some, but not all, are blocked by the peptide toxin apamin, and apamin-sensitive channels are also blocked by d-tubocurarine. Cloned SK channels (small conductance calcium-activated potassium channel) recapitulate these properties. We have investigated the structural basis for these differences and found that two amino acid residues on either side of the deep pore are the primary determinants of sensitivity to apamin and differential block by d-tubocurarine. Therefore, the pharmacology of SK channels compared with other potassium channels correlates with structural differences in the outer pore region. However, introduction of a tyrosine residue in the position analogous to that which determines sensitivity to external tetraethylammonium for voltagegated potassium channels endows SK channels with an equivalent tetraethylammonium sensitivity, indicating that the outer vestibules of the pores are similar. The pharmacology of channels formed in oocytes coinjected with SK1 and SK2 mRNAs, or with SK1-SK2 dimer mRNA, show that SK subunits may form heteromeric channels.Small conductance calcium-activated potassium channels (SK channels) 1 are responsible for the slow afterhyperpolarization (sAHP) following an action potential. With sustained stimulus, spike frequency adaptation occurs where the repetitive firing of action potentials is self-limiting, because the depth and time course of the sAHP are extended, preventing the membrane potential from reaching threshold (1-4). The sAHP demonstrates a distinct pharmacology. In hippocampal interneurons, the sAHP is blocked by the peptide toxin, apamin (5, 6), while in pyramidal cells, it is not affected (7). Apaminsensitive sAHPs (8, 9) and SK channels (10) are also sensitive to the plant alkyloid, d-tubocurarine (dTC). Therefore, the structural relationship between the channels underlying apamin-sensitive and apamin-insensitive sAHPs was unclear.Recently, the amino acid sequences of several SK channels have been described (11). Compared with other cloned K ϩ channels, and consistent with their distinct pharmacology and biophsyical properties, SK channels form a separate branch of the potassium channel family tree. They show no clear homology to other K ϩ channels except in part of the pore region. Heterologously expressed SK2 channels are blocked by apamin with an IC 50 of 60 pM, while highly homologous SK1 channels are not blocked by 100 nM apamin. Also, SK2 channels are more sensitive to dTC than SK1 channels (11). In situ hybridization studies in rat brain showed a good correlation between the pattern of apamin-sensitive SK channel mRNAs, SK2 and SK3, and radiolabeled apamin binding sites, while SK1 mRNA was detected in cell types with apamin-insensitive AHPs (11-14).Apamin-sensitive SK channels have been implicated in several important physiological processes. In the central nervous system, the sensory motor portion of the inferior colliculis is capable of seizure generating activity,...

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“…Intrathecal or systemic administration of apamin has been shown to enhance learning and memory responses in both mice and rats. [195][196][197][198] Taken together with the observation that mice overexpressing K Ca 2.2 exhibit impaired hippocampal learning and memory, 176 these findings suggest that selective K Ca 2.2 blockers might be able to function as "memory enhancers" and improve cognitive performance in dementia. However, higher doses of systemically administered apamin induce seizures cautioning that the therapeutic window for this application might be narrow.…”

Section: K Ca 2 Channel Blockersmentioning

confidence: 95%

K⁺ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases

2008

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Effect of apamin, a toxin that inhibits Ca2+-dependent K+ channels, on learning and memory processes

Cited by 114 publications

References 17 publications

An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

Determinants of Apamin and d-Tubocurarine Block in SK Potassium Channels

K⁺ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases

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Effect of apamin, a toxin that inhibits Ca2+-dependent K+ channels, on learning and memory processes

Cited by 114 publications

References 17 publications

An apamin-sensitive Ca 2+ -activated K + current in hippocampal pyramidal neurons

An apamin-sensitive Ca 2+ -activated K + current in hippocampal pyramidal neurons

Determinants of Apamin and d-Tubocurarine Block in SK Potassium Channels

K+ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases

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Product

Resources

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An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

An apamin-sensitive Ca ²⁺ -activated K ⁺ current in hippocampal pyramidal neurons

K⁺ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases