Apamin

Apamin-Sensitive Small Conductance Calcium-Activated Potassium Channels were Negatively Regulated by Captopril in Volume-Overload Heart Failure Rats.[Pubmed:26924798]

J Membr Biol. 2016 Aug;249(4):429-36.

In heart failure (HF), the malignant arrhythmias occur frequently; a study demonstrated that upregulation of I KAS resulted in recurrent spontaneous ventricular fibrillation in HF. However, the regulation of SK channels was poorly understood. The activation of SK channels depended on [Ca(2+)]i and PP2A; studies suggested that angiotensin II can regulate them. So, we hypothesized that in HF, the excess of angiotensin may regulate the SK channels and result in the remodeling of SK channels. To test the hypothesis, we used volume-overload-induced HF rat model, treated with captopril, performed whole-cell patch clamp to record Apamin-sensitive currents (I KAS), and I-V curve was studied. The sensitivity of I KAS to [Ca(2+)]i was also explored by setting various [Ca(2+)]i (10, 100, 500, 900, 1000, and 10,000 nM), and the steady-state Ca(2+) response of I KAS was attained and performed Hill fitting with the equation (y = 1/[1 + (EC50/x) (n) ]). Immunofluorescent staining, real-time PCR, Western blot were also carried out to furtherly investigate the underlying molecular mechanisms of the regulation. Captopril significantly decreased the mean density of I KAS when [Ca(2+)]i was 500, 900, 1000, and 10000 nM. The Hill fitting showed significantly different EC50 values and the Hill coefficients and showed captopril significantly shifted rightward the steady-state Ca(2+) response of I KAS. The results of real-time PCR and Western blot demonstrated captopril decreased the mRNA and protein expression of SK3 channels. Captopril significantly downregulated the sensitivity of SK channels to [Ca(2+)]i and the SK3 channels expression in HF, and reversed the SK channels remodeling.

Apamin Boosting of Synaptic Potentials in CaV2.3 R-Type Ca2+ Channel Null Mice.[Pubmed:26418566]

PLoS One. 2015 Sep 29;10(9):e0139332.

SK2- and KV4.2-containing K+ channels modulate evoked synaptic potentials in CA1 pyramidal neurons. Each is coupled to a distinct Ca2+ source that provides Ca2+-dependent feedback regulation to limit AMPA receptor (AMPAR)- and NMDA receptor (NMDAR)-mediated postsynaptic depolarization. SK2-containing channels are activated by Ca2+ entry through NMDARs, whereas KV4.2-containing channel availability is increased by Ca2+ entry through SNX-482 (SNX) sensitive CaV2.3 R-type Ca2+ channels. Recent studies have challenged the functional coupling between NMDARs and SK2-containing channels, suggesting that synaptic SK2-containing channels are instead activated by Ca2+ entry through R-type Ca2+ channels. Furthermore, SNX has been implicated to have off target affects, which would challenge the proposed coupling between R-type Ca2+ channels and KV4.2-containing K+ channels. To reconcile these conflicting results, we evaluated the effect of SK channel blocker Apamin and R-type Ca2+ channel blocker SNX on evoked excitatory postsynaptic potentials (EPSPs) in CA1 pyramidal neurons from CaV2.3 null mice. The results show that in the absence of CaV2.3 channels, Apamin application still boosted EPSPs. The boosting effect of CaV2.3 channel blockers on EPSPs observed in neurons from wild type mice was not observed in neurons from CaV2.3 null mice. These data are consistent with a model in which SK2-containing channels are functionally coupled to NMDARs and KV4.2-containing channels to CaV2.3 channels to provide negative feedback regulation of EPSPs in the spines of CA1 pyramidal neurons.

The small neurotoxin apamin blocks not only small conductance Ca(2+) activated K(+) channels (SK type) but also the voltage dependent Kv1.3 channel.[Pubmed:28108814]

Eur Biophys J. 2017 Sep;46(6):517-523.

Apamin is frequently used as a specific blocker of small-conductance Ca(2+)-activated (SK type) K(+) channels. Here we show that the small neurotoxin is not as specific as anticipated. It is also a high-affinity inhibitor with an IC50 of 13 nM of the Kv1.3 channel; it blocks the latter with potency similar to the Kv1.3 blocker PAP-1. Since SK type channels and Kv1.3 channels are frequently coexpressed in different tissues such as cells of the immune system, Apamin must be used with caution as a pharmacological tool.

Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts.[Pubmed:28213506]

Circ Arrhythm Electrophysiol. 2017 Feb;10(2):e004434.

BACKGROUND: Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents (IKAS) are heterogeneously upregulated in failing hearts. We hypothesized that IKAS influences the location and stability of rotors during VF. METHODS AND RESULTS: Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after Apamin (100 nmol/L) infusion, the action potential duration (APD80) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (DeltaAPD) after Apamin infusion were considered to have a high IKAS distribution. At baseline, the distribution density of phase singularities during VF in high IKAS distribution areas was higher than in other areas (0.0035+/-0.0011 versus 0.0014+/-0.0010 phase singularities/pixel; P=0.004). In addition, high dominant frequencies also colocalized to high IKAS distribution areas (26.0 versus 17.9 Hz; P=0.003). These correlations were eliminated during VF after Apamin infusion, as the number of phase singularities (17.2 versus 11.0; P=0.009) and dominant frequencies (22.1 versus 16.2 Hz; P=0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after Apamin infusion, and the duration of VF decreased. CONCLUSIONS: The IKAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high IKAS. Apamin eliminated this relationship and reduced VF vulnerability.

Matching molecules to function: neuronal Ca2+-activated K+ channels and afterhyperpolarizations.[Pubmed:15208027]

Toxicon. 2004 Jun 15;43(8):933-49.

Potassium channels regulate the membrane excitability of neurons, play a major role in shaping action potentials, determining firing patterns and regulating neurotransmitter release, and thus significantly contribute to neuronal signal encoding and integration. This review focuses on the molecular and cellular basis for the specific function of small-conductance calcium-activated potassium channels (SK channels) in the nervous system. SK channels are activated by an intracellular increase of free calcium during action potentials. They mediate currents that modulate the firing frequency of neurons. Three SK channel subunits have been cloned and form channels, which are voltage-insensitive, activated by submicromolar intracellular calcium concentrations, and are blocked, with different affinities, by a number of toxins and organic compounds. Different neurons in the central and peripheral nervous system express distinct subsets of SK channel subunits. Recent progress has been made in relating cloned SK channels to their native counterparts. These findings argue in favour of regulatory mechanisms conferring to native SK channels with specific subunit compositions distinct and specific functional profiles in different neurons.

Behavioral effects of apamin, a selective inhibitor of the SK(Ca)-channel, in mice and rats.[Pubmed:10643819]

Neurosci Biobehav Rev. 1999 Dec;23(8):1087-110.

Apamin, a highly selective and potent peptide that blocks the SK(Ca)-channels has been suggested to be a cognition enhancer. We tested Apamin in the Morris water escape task, in shock motivated avoidance tasks, and in operant tasks in the Skinnerbox. We also used non-cognitive tests, such as the rat forced swimming test and cocaine-induced locomotor activity in the open field, and a test to assess the side effect profile. Mice and rats from different strains, and rats of different ages were used. The rat studies provided only weak support for the notion that Apamin acts as a cognition enhancer. More convincing evidence was obtained from the mouse studies. Overt side effects of Apamin were found at the dose of 0.3 mg kg(-1). This dose was close to, or even overlapped, the doses which improved cognition in mice. We conclude that Apamin is a poor tool to assess the role of SK(Ca)-channels in learning and memory processes.

Potassium channel toxins.[Pubmed:2181489]

Pharmacol Ther. 1990;46(1):137-62.

Many venom toxins interfere with ion channel function. Toxins, as specific, high affinity ligands, have played an important part in purifying and characterizing many ion channel proteins. Our knowledge of potassium ion channel structure is meager because until recently, no specific potassium channel toxins were known, or identified as such. This review summarizes the sudden explosion of research on potassium channel toxins that has occurred in recent years. Toxins are discussed in terms of their structure, physiological and pharmacological properties, and the characterization of toxin binding sites on different subtypes of potassium ion channels.

Apamin (Apamine) is an 18 amino acid peptide neurotoxin found in apitoxin (bee venom), is known as a specifically selective blocker of Ca2+-activated K+ (SK) channels and exhibits anti-inflammatory and anti-fibrotic activity.

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