Summary

Paper summary

The CTD was elucidated from a 3.0 angstrom resolution x-ray diffraction patten. This structure contains two tandem RCK domains and each RCK domain contains a big lobe, a helix-turn-helix connector and a small lobe. The helix-turn-helix connector works as a clasp to join RCK1 and RCK2 together. The calcium bowl is located within the RCK2 domain.

The tetrameric structure was postulated through the use of a 6 angstrom resolution x-ray diffraction pattern of a homologue.

As we have seen the BK human channel has been postulated based on homologous potassium channels. However, this is a speculative structure since the actual x-ray structure is yet to be elucidated due to the difficulties in analyzing membrane proteins.

Implications 

In ischemic strokes, the blood supply to parts of the brain is reduced, leading to dysfunction in the affected area. During this period a fatal biochemical cascade that produces neuronal hyperexcitability is unleashed. This hyperexcitability is caused when neurons at risk are exposed to excessive excitatory amino acids and dangerously high levels of intracellular Calcium. Since the human BK channel is one of the key players in neuronal hyperpolarization (and therefore is involved in the decrease of intracellular Calcium channel as well as "inactivation" of the neuron), theoretically, it should be possible to decrease the effects of the neurotoxic levels of calcium by creating a drug that targets the BK channel and transiently stabilizes its open conformation. However, a drug developed by Bristol-Myers Squibb failed to improve the clinical outcome in stroke patients. Therefore, in order for us to discover a way of decreasing the detrimental effects of a stroke, we must first understand the BK channel and other similar channels in greater detail.

Further research

There are three regions where mutations have large adverse effects on the function of the human BK channel:

1) Regional group surrounding the calcium bowl - mutation leads to loss of sensitivity towards calcium
2) Helix-turn-helix connector region - probably affect conformational changes once calcium binds to the calcium bowl.
3) N-terminus region of RCK1 (surface of the CTD that faces the voltage sensor in the complete BK channel model).

The pore is controlled directly by the calcium binding through a conformational change through the S6 helix connection and is also controlled by voltage through the S4-S5 linker voltage sensor. The third group of mutations raise interesting possibilities of additional interactions between the CTD and the voltage sensor. An experiment has even identified a magnesium ion bridging the amino acids of these two regions!

References

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