BK channel

Edit links
Source: Wikipedia, the free encyclopedia.
Chr. 10 q22
Search for
StructuresSwiss-model
DomainsInterPro
Chr. 5 q34
Search for
StructuresSwiss-model
DomainsInterPro
Chr. 3 q26.32
Search for
StructuresSwiss-model
DomainsInterPro
BK Channel Diagram
BK Channel Structure
Chr. 3 q26.3-q27
Search for
StructuresSwiss-model
DomainsInterPro
KCNMB3L
Identifiers
SymbolKCNMB3L
Alt. symbolsKCNMB2L, KCNMBLP
Chr. 22 q11.1
Chr. 12 q15
Search for
StructuresSwiss-model
DomainsInterPro
Calcium-activated BK potassium channel alpha subunit
Identifiers
SymbolBK_channel_a
PfamPF03493
InterProIPR003929
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

BK channels (big potassium), are large conductance calcium-activated potassium channels,

X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization
or increase in calcium levels.

Structure

Structurally, BK channels are homologous to

KCNMA1
gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function:

The activation gate resides in the PGD, which is located at either the cytosolic side of S6 or the selectivity filter (selectivity is the preference of a channel to conduct a specific ion).

voltage sensor.[6]

BK channels are quite similar to voltage gated K⁺ channels, however, in BK channels only one positively charged residue (Arg213) is involved in voltage sensing across the membrane.[5] Also unique to BK channels is an additional S0 segment, this segment is required for β subunit modulation.[7][8] and voltage sensitivity.[9]

The Cytosolic domain is composed of two RCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinity

smooth muscle cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within the brain.[5]
The VSD associates with the PGD via three major interactions:

  1. Physical connection between the VSD and PGD through the S4-S5 linker.
  2. Interactions between the S4-S5 linker and the cytosolic side of S6.
  3. Interactions between S4 and S5 of a neighboring subunit.

Regulation

BK channels are associated and modulated by a wide variety of intra- and extracellular factors, such as auxiliary subunits (β, γ), Slobs (slo binding protein),

membrane voltage, chemical ligands (Ca²⁺, Mg²⁺), PKC, The BK α-subunits assemble 1:1 with four different auxiliary types of β-subunits (β1, β2, β3 or β4).[10]

Trafficking to and expression of BK channels in the

splice variant that excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impacts physiology and pathophysiology.[10]

BK channels in the

angiotensin II (Ang II), high glucose or arachidonic acid (AA) which is modulated in diabetes by oxidative stress (ROS).[10]

A weaker voltage sensitivity allows BK channels to function in a wide range of membrane potentials. This ensures that the channel can properly perform its physiological function.[11]

Inhibition of BK channel activity by phosphorylation of S695 by protein kinase C (PKC) is dependent on the phosphorylation of S1151 in C terminus of channel alpha-subunit. Only one of these phosphorylations in the tetrameric structure needs to occur for inhibition to be successful. Protein phosphatase 1 counteracts phosphorylation of S695. PKC decreases channel opening probability by shortening the channel open time and prolonging the closed state of the channel. PKC does not affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels.[11]

Activation mechanism

BK channels are

voltage sensors and the Ca²⁺ bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. The Ca²⁺ bowl accelerates activation kinetics at low Ca²⁺ concentrations while RCK1 site influences both activation and deactivation kinetics.[11] One mechanism model was originally proposed by Monod, Wyman, and Changeux, known as the MWC model. The MWC model for BK channels explains that a conformational change of the activation gate in channel opening is accompanied by a conformational change to the Ca²⁺ binding site, which increases the affinity of Ca²⁺ binding.[12]

Magnesium-dependent activation of BK channels activates via a low-affinity metal binding site that is independent from Ca²⁺-dependent activation. The Mg²⁺ sensor activates BK channels by shifting the activation voltage to a more negative range. Mg²⁺ activates the channel only when the voltage sensor domain stays in the activated state. The cytosolic tail domain (CTD) is a chemical sensor that has multiple binding sites for different

ion conduction through the pore.[5]

Effects on the neuron, organ, body as a whole

Cellular level

BK channels help regulate both the firing of

methionine oxidation.[10]

Organ level

BK channels also play a role in

seizures in the temporal lobe.[10]

Bodily function level

Mutations of BK channels, resulting in a lower amount of expression in

cancer therapy, discussed more in the pharmacology section.[10]
BK channels are ubiquitous throughout the body and thus have a large and vast impact on the body as a whole and at a more cellular level, as discussed.

Pharmacology

Potential issues

Several issues arise when there is a deficit in BK channels. Consequences of the malfunctioning BK channel can affect the functioning of a person in many ways, some more life-threatening than others. BK channels can be activated by exogenous pollutants and endogenous

resting membrane potential.[10]
Thus, understanding is crucial for safety in effective transplantation.

Current developments

BK channels can be used as

knockout mice, a model of Fragile X syndrome.[23][24] BK channels also function as a blocker in ischemia and are a focus in investigating its use as a therapy for stroke.[10]

Future directions

There are many applications for therapeutic strategies involving BK channels. There has been research displaying that a blockage of BK channels results in an increase in neurotransmitter release, effectively indicating future therapeutic possibilities in

alcoholics. Oxidative stress on BK channels can lead to the negative impairments of lowering blood pressure through cardiovascular relaxation have on both aging and disease.[10] Thus, the signaling system can be involved in treating hypertension and atherosclerosis[10] through targeting of the ɑ subunit to prevent these detrimental effects. Furthermore, the known role that BK channels can play in cancer and tumors is limited. Thus, there is not a lot of current knowledge regarding specific aspects of BK channels that can influence tumors and cancers.[14] Further study is crucial, as this could lead to immense development in treatments for those with cancer and tumors. It is known that epilepsies are due to over-excitability of neurons, which BK channels have a large impact on controlling hyperexcitability.[4]
Therefore, understanding could influence the treatment of epilepsy. Overall, BK channels are a target for future pharmacological agents that can be used for benevolent treatments of disease.

See also

References

  1. S2CID 4663325
    .
  2. ^ Miller, C. (2000). Genome Biology, 1(4), reviews0004.1. https://dx.doi.org/10.1186/gb-2000-1-4-reviews0004
  3. ^ Yuan, P., Leonetti, M., Pico, A., Hsiung, Y., & MacKinnon, R. (2010). Structure of the Human BK Channel Ca2+-Activation Apparatus at 3.0 A Resolution. Science, 329(5988), 182-186. https://dx.doi.org/10.1126/science.1190414
  4. ^
    PMID 21923633
    .
  5. ^
    PMID 20663573
    .
  6. S2CID 11317087
    .
  7. PMID 16549765
    .
  8. PMID 8962157
    .
  9. PMID 17296928
    .
  10. ^
    PMID 26287261
    .
  11. ^
    PMID 25705194
    .
  12. ^
    PMID 19099186
    .
  13. ^
    PMID 26725735
    .
  14. ^
    PMID 25346695
    .
  15. ^
    PMID 27238267
    .
  16. PMID 15664403
    .
  17. PMID 18316727
    .
  18. S2CID 23073556
    .
  19. S2CID 8791803
    .
  20. PMID 19923353
    .
  21. S2CID 10236998
    .
  22. PMID 12481191
    .
  23. S2CID 25225269
    .
  24. PMID 25079250
    .

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=BK_channel&oldid=1211238635"