Calcium-Activated Potassium Channels: Multiple Contributions to Neuronal Function

E.S. Louise Faber and Pankaj SahPPT by Anvinh Nguyen

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.

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.

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

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

BK Channel Enhancement and Inhibition

• BK Channels are enhanced by Dehydrosoyasaponin-1 (DHS-1)

• BK Channels are inhibited by TEA

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

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

IK Channels

• Conductance of 20 to 100 pS• Identified in epithelial and red blood cells• Activated by intracellular calcium, and are

voltage insensitive

IK Channel Enhancement and Inhibition

• IK Channels are also enhanced by 1-ethyl-2-benzimidazolinone (EBIO)

• IK Channels are inhibited by certain neurotransmitters

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

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

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

Fast AHP

Introduction of paxilline (could also be TEA) would cause a reduction in the fast AHP.

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.

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

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

Slow AHP

Adding noradrenaline causes the slow AHP to be reduced.

This also resulted in a reduction in spike frequency adaptation.

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

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

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.

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.