Potassium Channels

SK

Small-conductance Ca2+-activated K+ channels

When do SK channels open?

When intracellular calcium binds to calmodulin (CaM) → triggers K+ efflux → neuronal repolarisation

SK1 Localisation

Neuronal soma and dendrites

SK1 Function

Modulates excitability

SK2 Localisation

Postsynaptic spines and mitochondria

SK2 Function

Neuroprotective subtype

SK3 Localisation

Broadly expressed including glia

SK3 Function

Involved in excitability and cognition

Which receptors does glutamate activate?

Ionotropic (NMDA, AMPA, and kainate) and metabotropic receptors

What does hyperactivity of glutamate lead to?

Excitotoxicity

Apamin Effect

Inhibitor

Apamin Mechanism

Bee venom peptide; blocks SK1-3 selectively

1-EBIO, NS309, CyPPA Effect

Positive modulators (activators)

1-EBIO, NS309, CyPPA Mechanism

Enhance SK activity → neuroprotection

SK inhibitory peptides effect

Blockers

SK inhibitory peptides mechanism

Experimental tools

Which SK channels does CyPPA activate?

SK2/SK3

What is Long Term Potentiation (LTP) important in?

Learning and memory

What does SK activation do in Middle cerebral artery occlusion (MCAO)

SK activation reduces infarct size (in stroke) and neuronal death

Which transporter does glutamate inhibit?

xCT transporter

What is the effect of glutamate inhibiting the xCT transporter?

Decreased cystine uptake → decreased glutathione (GSH) → increased ROS → mitochondrial damage

What does CyPPA activation of SK channels preserve?

Mitochondrial morphology and membrane potential

What does CyPPA activation of SK channels reduce?

AIF, cytochrome c, Smac/Diablo release

Where in the mitochondria are SK2 channels localised in?

Inner mitochondrial membrane (IMM) of neurons

How was SK2 channels being localised in the IMM confirmed?

via patch clamp of mitoplasts

Overexpressing mitochondrial SK2-EGFP outcome

Strong protection against glutamate toxicity

Dominant-negative SK2 mutant outcome

Lost protection, increased cell death

What does controlled mitochondrial SK activity lead to?

Reduced metabolic stress and enhanced longevity

What do SK channels in the ER membrane do?

Mediate K+ influx into ER lumen, supporting ER Ca2+ uptake

Which metabolite can induce ER stress?

Brefeldin A

What does CyPPA do under ER stress?

Decrease caspase-3 and caspase-12 cleavage

Er-mitochondria contact sites (MAMs) function

Regulate Ca2+ transfer and cell survival

What does excessive MAM coupling lead to?

Ca2+ overload and cell death

What does CyPPA do in terms of MAMs?

Reduces MAM contact sites, preventing Ca2+ overtransfer → neuroprotection

What does microglial overactivation contribute to?

Neurodegeneration

What does CyPPA do in terms of microglial activation?

• Reduces microglial morphological changes

• Decreases TNF-α, IL-1β, IL-6 release

• Attenuates α-synuclein-induced microglial activation

What happens to the metabolism during mitochondrial dysfunction?

Switch to glycolysis (Warburg-like) in activated microglia

What does SK activation modulate in terms of metabolism?

Modulates glycolytic vs oxidative balance