1. Calcium-Activated Potassium Channels: Multiple Contributions to Neuronal Function E.S. Louise Faber and Pankaj Sah PPT by Anvinh Nguyen

2. 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.

3. 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.

4. 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

5. 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

6. BK Channel Enhancement and Inhibition BK Channels are enhanced by Dehydrosoyasaponin-1 (DHS-1) BK Channels are inhibited by TEA

7. 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

8. 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

9. IK Channels Conductance of 20 to 100 pS Identified in epithelial and red blood cells Activated by intracellular calcium, and are voltage insensitive

10. IK Channel Enhancement and Inhibition IK Channels are also enhanced by 1-ethyl-2- benzimidazolinone (EBIO) IK Channels are inhibited by certain neurotransmitters

11. 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

12. 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

13. 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

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

15. 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.

16. Medium AHP Apamin blocks SK Channels which causes a reduction in the medium AHP. This causes: Higher firing frequency Decrease in spike frequency adaptation In figure A, slow AHP is still there, only medium AHP was reduced

17. 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

18. Slow AHP Adding noradrenaline causes the slow AHP to be reduced. This also resulted in a reduction in spike frequency adaptation.

19. 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

20. 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

21. 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.

22. 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.