Calcium-Activated Potassium Channels: Multiple Contributions to Neuronal Function
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Calcium-Activated Potassium Channels: Multiple Contributions to Neuronal Function
E.S. Louise Faber and Pankaj SahPPT by Anvinh Nguyen
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Calcium-activated Potassium Channels
– Found throughout CNS – Activated by rises in cytosolic calcium during AP– These channels are targets for modulation
because they have been thought to influence neurological and psychiatric disorders.
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First Identification of calcium-dependent potassium channels…
• By Gardos – he worked with red blood cells.
• By Meech and Strumwasser – they described an ionic current activated by a rise in cytosolic calcium.
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Three Types of Calcium-activated Potassium Channels
• 1. BK Channels– First type identified and cloned– Highly potassium selective and large conductance
• 2. SK Channels– Fairly low conductance
• 3. IK Channels – Intermediate conductance
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BK Channels
• Large conductances 200 to 400 pS• Requires both intracellular calcium and
depolarization• Surprisingly, can open without calcium
calcium and voltage are independent processes
• α (tetramer, pore-forming) and β (three subunits) subunits
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BK Channel Enhancement and Inhibition
• BK Channels are enhanced by Dehydrosoyasaponin-1 (DHS-1)
• BK Channels are inhibited by TEA
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SK Channels
• Three types have been successfully cloned: SK1, SK2, and SK3
• Conductance of 2 to 20 pS• Activated by intracellular calcium, and are
voltage insensitive• SK pore is similar to the voltage-gated potassium
channel’s pore – Must both be transmembrane bound proteins with
tetramer pore
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SK Channel Enhancement and Inhibition
• SK Channels are enhanced by 1-ethyl-2-benzimidazolinone (EBIO)– It works by changing calcium sensitivity and open
probability
• SK Channels are inhibited by Apamin, a type of bee venom
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IK Channels
• Conductance of 20 to 100 pS• Identified in epithelial and red blood cells• Activated by intracellular calcium, and are
voltage insensitive
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IK Channel Enhancement and Inhibition
• IK Channels are also enhanced by 1-ethyl-2-benzimidazolinone (EBIO)
• IK Channels are inhibited by certain neurotransmitters
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Afterhyperpolarization (AHP)
• AHP follows an action potential in many neurons
• They can last up to several seconds• All cases: slow component AHP from calcium-
activated potassium conductance• Some cases: intracellular calcium release helps
activate AHP
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Types of AHPs• Fast:• 1. Fast
• Slow:• 2. Medium• 3. Slow
• Fast AHP responsible for:– Repolarization
• Slow (medium and slow) AHP responsible for: – limiting firing frequency– Generating spike-frequency adaptation
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Fast AHP
• Mediate by calcium-activated potassium currents– Calcium and depolarization
• Blocked by TEA, so BK channel is most likely the one
• Modulated by PKA through phosphorylation– Upreg or downreg is based on the channel
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Fast AHP
Introduction of paxilline (could also be TEA) would cause a reduction in the fast AHP.
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Medium AHP
• Mediate by calcium-activated potassium currents– Calcium only
• It is blocked by apamin, not TEA, suggesting SK channel
• Expression of SK1, SK2, and SK3 resulted in the same result as the medium AHP
• Does not influence repolarization like the fast AHP.
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Medium AHP
Apamin blocks SK Channels which causes a reduction in the medium AHP. This causes:
Higher firing frequencyDecrease in spike frequency adaptation
In figure A, slow AHP is still there, only medium AHP was reduced
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Slow AHP
• More commonly seen in AP trains than single AP’s• Slow AHP is not blocked by either TEA or apamin• Slow AHP is modulated by a range of
neurotransmitters IK channel– Monoamines can activate PKA or inhibit calcium-
induced calcium release. • It is responsible for spike frequency adaptation
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Slow AHP
Adding noradrenaline causes the slow AHP to be reduced.
This also resulted in a reduction in spike frequency adaptation.
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Functional Role: Medium AHP
• Blockade of SK channels with apamin learning in a number of behavioral studies
• Effects the acquisition of learning the task, not the consolidation
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Functional Role: Slow AHP
• Reduction in the Slow AHP reduction in spike frequency adaptation
• Inhibition of Slow AHP increased excitability during learning and neuronal plasticity
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Aging
• Drugs that depress the slow AHP, such as calcium channel blockers have shown to effectively improve learning in aged animals.
• Further studies show that an increase in medium AHP reduced ability of hippocampal neurons from aged animals to undergo synaptic plasticity.
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Disease
• Apamin binding sites reduced in hippocampus brains from patients with Alzheimer’s disease
• Slow AHP has been proposed to reduce excitability to prevent onset of epilepsy in CA1 hippocampal neurons.