Small conductance calcium-activated potassium channels (SK) are a family of voltage-independent potassium channels with a distinct physiology and pharmacology. The three members (SK1, SK2 and SK3) of the SK channel subfamily are characterized by similar biophysical properties, because all SK channels show a small single channel conductance and are activated by rises in intracellular calcium that gate the channels upon binding to the constitutively associated calcium sensor calmodulin. All three SK channels are expressed in the brain and show a differential distribution. The SK channel-mediated current (IAHP) has been studied in various regions of the central nervous system, where it regulates membrane excitability, increases the precision of neuronal firing, and modulates synaptic plasticity.

Toxins from animal venoms form the largest group of high affinity potassium channel blockers and are useful pharmacological tools to investigate structure-function relations and to study their physiological role. The molecular correlation between native SK currents and their molecular counterparts was facilitated by the 18-amino acid bee venom toxin apamin, a specific blocker for which the only known receptor are the SK channels. Our interest in identifying a functional role for the rat SK1 channel led to an investigation in the differences of apamin pharmacology between members of the SK channel family and revealed a novel mechanism of ion channel inhibition whereby, in contrast to other potassium channels, not only amino acids in the pore region influence their toxin sensitivity.

Besides toxins and small molecule inhibitors, SK channel enhancers have proven to be precious tools for the elucidation of the function of these channels in different brain regions and have opened new therapeutic avenues for the treatment of disorders linked to neuronal hyperexcitability.

This talk will summarize our present knowledge on SK channel molecular and cellular physiology and illustrate how a combination of molecular biology, pharmacology and electrophysiology is helping us understanding the multifaceted roles of these channels in the brain.

Acknowledgements:

We thank Dr P. Pedarzani (UCL Neuroscience, Physiology and Pharmacology) for valuable discussion.