Wikipedia

BK channel

BK channels(big potassium), arelarge conductance calcium-activated potassium channels,[1]also known asMaxi-K,slo1,orKca1.1.BK channels arevoltage-gated potassium channelsthat conduct large amounts ofpotassium ions(K+) across thecell membrane,hence their name,big potassium.These channels can be activated (opened) by either electrical means, or by increasingCa2+concentrations in the cell.[2][3]BK channels help regulate physiological processes, such ascircadian behavioral rhythmsand neuronal excitability.[4]BK channels are also involved in many processes in the body, as it is aubiquitouschannel. They have a tetrameric structure that is composed of atransmembrane domain,voltage sensingdomain,potassium channeldomain, and acytoplasmicC-terminal domain,with manyX-ray structuresfor reference. Their function is torepolarizethe membrane potential by allowing for potassium to flow outward, in response to adepolarizationor increase in calcium levels.

KCNMA1
The domain structure of BK channels
Identifiers
SymbolKCNMA1
Alt. symbolsSLO
NCBI gene3778
HGNC6284
OMIM600150
RefSeqNM_002247
UniProtQ12791
Other data
LocusChr. 10q22
Search for
StructuresSwiss-model
DomainsInterPro
KCNMB1
Identifiers
SymbolKCNMB1
NCBI gene3779
HGNC6285
OMIM603951
RefSeqNM_004137
UniProtQ16558
Other data
LocusChr. 5q34
Search for
StructuresSwiss-model
DomainsInterPro
KCNMB2
Identifiers
SymbolKCNMB2
NCBI gene10242
HGNC6286
OMIM605214
RefSeqNM_181361
UniProtQ9Y691
Other data
LocusChr. 3q26.32
Search for
StructuresSwiss-model
DomainsInterPro
BK Channel Diagram
BK Channel Structure
KCNMB3
Identifiers
SymbolKCNMB3
Alt. symbolsKCNMB2, KCNMBL
NCBI gene27094
HGNC6287
OMIM605222
RefSeqNM_171828
UniProtQ9NPA1
Other data
LocusChr. 3q26.3-q27
Search for
StructuresSwiss-model
DomainsInterPro
KCNMB3L
Identifiers
SymbolKCNMB3L
Alt. symbolsKCNMB2L, KCNMBLP
NCBI gene27093
HGNC6288
RefSeqNG_002679
Other data
LocusChr. 22q11.1
KCNMB4
Identifiers
SymbolKCNMB4
NCBI gene27345
HGNC6289
OMIM605223
RefSeqNM_014505
UniProtQ86W47
Other data
LocusChr. 12q15
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

Structure

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Structurally, BK channels are homologous tovoltage- andligand-gatedpotassium channels,having avoltage sensorand pore as themembrane-spanningdomain and acytosolicdomain for the binding of intracellularcalciumandmagnesium.[5]Eachmonomerof the channel-forming alpha subunit is the product of theKCNMA1gene (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).[5]The voltage sensing domain and pore-gated domain are collectively referred as themembrane-spanningdomains and are formed bytransmembranesegments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primaryvoltage sensor.[6]

BK channels are quite similar tovoltage 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 subunitmodulation.[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 affinityCa²⁺binding sites:one in the RCK1 domain and the other in a region termed the Ca²⁺ bowl that consists of a series ofAspartic acid(Asp) residues that are located in the RCK2 domain. TheMg²⁺binding site is located between the VSD and the cytosolic domain, which is formed by: Asp residues within the S0-S1 loop,Asparagineresidues in the cytosolic end of S2, andGlutamineresidues in RCK1.[5]In forming theMg²⁺binding site, two residues come from the RCK1 of one Slo1 subunit and the other two residues come from the VSD of the neighboring subunit. In order for these residues to coordinate the Mg²⁺ ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity.[5]Modulatory beta subunits (encoded byKCNMB1,KCNMB2,KCNMB3,orKCNMB4) can associate with thetetrameric channel.There are four types of β subunits (β1-4), each of which have different expression patterns that modify the gating properties of the BK channel. The β1 subunit is primarily responsible forsmooth muscle cellexpression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within thebrain.[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

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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),phosphorylation,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 theplasma membranehas been found to be regulated by distinct splicing motifs located within theintracellularC-terminal RCK domains. In particular asplice variantthat excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impactsphysiologyandpathophysiology.[10]

BK channels in thevascular systemare modulated by agents naturally produced in the body, such asangiotensin II(Ang II),high glucoseorarachidonic acid(AA) which is modulated indiabetesbyoxidative 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 byphosphorylationof S695 byprotein 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 1counteracts phosphorylation of S695.PKCdecreases channel opening probability by shortening the channel open time and prolonging the closed state of the channel.PKCdoes not affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels.[11]

Activation mechanism

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BK channels aresynergisticallyactivated through the binding ofcalciumandmagnesiumions, but can also be activated via voltage dependence.[10]Ca²⁺ - dependent activation occurs when intracellular Ca²⁺ binds to two high affinitybinding sites:one located in theC-terminusof the RCK2 domain (Ca²⁺ bowl), and the other located in the RCK1 domain.[5]The binding site within the RCK1 domain has somewhat of a lower affinity for calcium than the Ca²⁺ bowl, but is responsible for a larger portion of the Ca²⁺ sensitivity.[12]Voltage and calcium activate BK channels using two parallel mechanisms, with thevoltage sensorsand 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 aconformational changeof the activation gate in channel opening is accompanied by aconformational changeto 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 differentligands.The CTD activates the BK channel when bound with intracellular Mg²⁺ to allow for interaction with thevoltage sensor domain(VSD).[11]Magnesium is predominantly coordinated by sixoxygenatoms from the side chains of oxygen-containing residues, main chaincarbonyl groupsinproteins,orwater molecules.[12]D99 at the C-terminus of the S0-S1 loop andN172in the S2-S3 loop contain side chain oxygens in the voltage sensor domain that are essential for Mg²⁺ binding. Much like the Ca²⁺-dependent activation model, Mg²⁺-dependent activation can also be described by an allosteric MCW gating model. While calcium activates the channel largely independent of the voltage sensor, magnesium activates the channel by channel by an electrostatic interaction with the voltage sensor.[12]This is also known as the Nudging model, in which Magnesium activates the channel by pushing the voltage sensor viaelectrostatic interactionsand involves the interactions amongside chainsin different structural domains.[5]Energy provided by voltage, Ca²⁺, and Mg²⁺ binding will propagate to the activation gate of BK channels to initiateion conductionthrough the pore.[5]

Effects on the neuron, organ, body as a whole

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Cellular level

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BK channels help regulate both the firing ofneuronsandneurotransmitterrelease.[13]This modulation ofsynaptic transmissionand electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels.[10]The opening of these channels causes a drive towards thepotassium equilibrium potentialand thus play a role in speeding up therepolarizationofaction potentials.[10]This would effectively allow for more rapid stimulation.[10]There is also a role played in shaping the general repolarization of cells, and thusafter hyperpolarization(AHP) of action potentials.[14]The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus.[14]It can also play a role in inhibiting the release of neurotransmitters.[15]There are many BK channels inPurkinje cellsin thecerebellum,thus highlighting their role inmotor coordinationand function.[14]Furthermore, BK channels play a role in modulating the activity ofdendritesas well asastrocytesandmicroglia.[15]They not only play a role in the CNS (central nervous system) but also insmooth muscle contractions,the secretion ofendocrine cells,and the proliferation of cells.[13]Various γ subunits during early brain development are involved in neuronal excitability and in non-excitable cells they often are responsible as a driving force of calcium.[10]Therefore, these subunits can be targets for therapeutic treatments as BK channel activators.[10]There is further evidence that inhibiting BK channels would prevent the efflux of potassium and thus reduce the usage ofATP,in effect allowing for neuronal survival in low oxygen environments.[10]BK channels can also function as a neuronal protectant in terms such as limiting calcium entry into the cells throughmethionine oxidation.[10]

Organ level

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BK channels also play a role inhearing.[14]This was found when the BK ɑ-subunit was knocked out inmiceand progressive loss of cochlear hair cells, and thus hearing loss, was observed.[14]BK channels are not only involved in hearing, but alsocircadian rhythms.Slo binding proteins (Slobs) can modulate BK channels as a function ofcircadian rhythmsin neurons.[10]BK channels are expressed in thesuprachiasmatic nucleus(SCN), which is characterized to influence thepathophysiologyof sleep.[14]BK channel openers can also have a protective effect on thecardiovascular system.[10]At a low concentration of calcium BK channels have a greater impact onvascular tone.[10]Furthermore, the signaling system of BK channels in the cardiovascular system have an influence on the functioning ofcoronary blood flow.[10]One of the functions of the β subunit in the brain includes inhibition of the BK channels, allowing for the slowing of channel properties as well as the ability to aid in prevention ofseizuresin thetemporal lobe.[10]

Bodily function level

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Mutations of BK channels, resulting in a lower amount of expression inmRNA,is more common in people who have mental disabilities (via hypofunction[15]),schizophreniaorautism.[10]Moreover, increasedrepolarizationcaused by BK channelmutationsmay lead to dependency of alcohol initiation ofdyskinesias,epilepsyor paroxysmal movement disorders.[10]Not only are BK channels important in many cellular processes in the adult it also is crucial for proper nutrition supply to a developingfetus.[10]Thus,estrogencan cause an increase in the density of BK channels in theuterus.[10]However, increased expression of BK channels have been found intumor cells,and this could influence futurecancer 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

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Potential issues

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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 endogenousgasotransmitterscarbon monoxide,[16][17]nitric oxide, and hydrogen sulphide.[18]Mutations in the proteins involved with BK channels orgenesencoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as:epilepsy,cancer,diabetes,asthma,andhypertension.[13]Specifically, β1 defect can increaseblood pressureand hydrosaline retention in thekidney.[13]Both loss of function and gain of function mutations have been found to be involved in disorders such as epilepsy andchronic pain.[15]Furthermore, increases in BK channel activation, throughgain-of-function mutantsand amplification, has links to epilepsy and cancer.[13]Moreover, BK channels play a role in tumors as well as cancers. In certain cancers gBK, a variant ion channel called glioma BK channel, can be found.[14]It is known that BK channels do in some way influence the division of cells duringreplication,which when unregulated can lead to cancers and tumors.[14]Moreover, an aspect studied includes the migration of cancer cells and the role in which BK channels can facilitate this migration, though much is still unknown.[14]Another reason why BK channel understanding is important involves its role inorgan transplantsurgery. This is due to the activation of BK channels influencing repolarization of theresting membrane potential.[10]Thus, understanding is crucial for safety in effective transplantation.

Current developments

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BK channels can be used aspharmacologicaltargets for the treatment of several medical disorders includingstroke[19]andoveractive bladder.[20]There have been attempts to develop synthetic molecules targeting BK channels,[21]however their efforts have proven largely ineffective thus far. For instance, BMS-204352, a molecule developed byBristol-Myers Squibb,failed to improve clinical outcome in stroke patients compared toplacebo.[22]However, there have been some success from theagonistto BKCa channels, BMS-204352, in treating deficits observed inFmr1knockout mice,a model ofFragile X syndrome.[23][24]BK channels also function as a blocker inischemiaand are a focus in investigating its use as a therapy for stroke.[10]

Future directions

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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 incognitionenhancement, improvedmemory,and relievingdepression.[13]A behavioral response to alcohol is also modulated by BK channels,[10]therefore further understanding of this relationship can aid treatment in patients who arealcoholics.Oxidative stresson 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 treatinghypertensionandatherosclerosis[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 toover-excitabilityof 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

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References

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  1. ^Zang K, Zhang Y, Hu J, Wang Y (2018). "The Large Conductance Calcium- and Voltage-activated Potassium Channel (BK) and Epilepsy".CNS & Neurological Disorders Drug Targets.17(4): 248–254.doi:10.2174/1871527317666180404104055.PMID29623857.S2CID4663325.
  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. ^abN'Gouemo P (November 2011)."Targeting BK (big potassium) channels in epilepsy".Expert Opinion on Therapeutic Targets.15(11): 1283–95.doi:10.1517/14728222.2011.620607.PMC3219529.PMID21923633.
  5. ^abcdefghiLee US, Cui J (September 2010)."BK channel activation: structural and functional insights".Trends in Neurosciences.33(9): 415–23.doi:10.1016/j.tins.2010.06.004.PMC2929326.PMID20663573.
  6. ^Atkinson NS, Robertson GA, Ganetzky B (August 1991). "A component of calcium-activated potassium channels encoded by the Drosophila slo locus".Science.253(5019): 551–5.Bibcode:1991Sci...253..551A.doi:10.1126/science.1857984.PMID1857984.S2CID11317087.
  7. ^Morrow JP, Zakharov SI, Liu G, Yang L, Sok AJ, Marx SO (March 2006)."Defining the BK channel domains required for beta1-subunit modulation".Proceedings of the National Academy of Sciences of the United States of America.103(13): 5096–101.Bibcode:2006PNAS..103.5096M.doi:10.1073/pnas.0600907103.PMC1458800.PMID16549765.
  8. ^Wallner M, Meera P, Toro L (December 1996)."Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus".Proceedings of the National Academy of Sciences of the United States of America.93(25): 14922–7.Bibcode:1996PNAS...9314922W.doi:10.1073/pnas.93.25.14922.PMC26238.PMID8962157.
  9. ^Koval OM, Fan Y, Rothberg BS (March 2007)."A role for the S0 transmembrane segment in voltage-dependent gating of BK channels".The Journal of General Physiology.129(3): 209–20.doi:10.1085/jgp.200609662.PMC2151615.PMID17296928.
  10. ^abcdefghijklmnopqrstuvwxyzHermann A, Sitdikova GF, Weiger TM (August 2015)."Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels".Biomolecules.5(3): 1870–911.doi:10.3390/biom5031870.PMC4598779.PMID26287261.
  11. ^abcdYang H, Zhang G, Cui J (2015)."BK channels: multiple sensors, one activation gate".Frontiers in Physiology.6:29.doi:10.3389/fphys.2015.00029.PMC4319557.PMID25705194.
  12. ^abcdCui J, Yang H, Lee US (March 2009)."Molecular mechanisms of BK channel activation".Cellular and Molecular Life Sciences.66(5): 852–75.doi:10.1007/s00018-008-8609-x.PMC2694844.PMID19099186.
  13. ^abcdefYu M, Liu SL, Sun PB, Pan H, Tian CL, Zhang LH (January 2016)."Peptide toxins and small-molecule blockers of BK channels".Acta Pharmacologica Sinica.37(1): 56–66.doi:10.1038/aps.2015.139.PMC4722972.PMID26725735.
  14. ^abcdefghijBentzen BH, Olesen SP, Rønn LC, Grunnet M (2014)."BK channel activators and their therapeutic perspectives".Frontiers in Physiology.5:389.doi:10.3389/fphys.2014.00389.PMC4191079.PMID25346695.
  15. ^abcdContet C, Goulding SP, Kuljis DA, Barth AL (2016). "BK Channels in the Central Nervous System".Big on Bk - Current Insights into the Function of Large Conductance Voltage- and Ca2+ -Activated K+ Channels at the Molecular, Cellular and Systemic Levels.International Review of Neurobiology. Vol. 128. pp. 281–342.doi:10.1016/bs.irn.2016.04.001.ISBN9780128036198.PMC4902275.PMID27238267.
  16. ^Dubuis E, Potier M, Wang R, Vandier C (Feb 2005)."Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels".Cardiovascular Research.65(3): 751–61.doi:10.1016/j.cardiores.2004.11.007.PMID15664403.
  17. ^Hou S, Xu R, Heinemann SH, Hoshi T (Mar 2008)."The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels".Proceedings of the National Academy of Sciences of the United States of America.105(10): 4039–43.Bibcode:2008PNAS..105.4039H.doi:10.1073/pnas.0800304105.PMC2268785.PMID18316727.
  18. ^Sitdikova GF, Weiger TM, Hermann A (Feb 2010). "Hydrogen sulfide increases calcium-activated potassium (BK) channel activity of rat pituitary tumor cells".Pflügers Archiv.459(3): 389–97.doi:10.1007/s00424-009-0737-0.PMID19802723.S2CID23073556.
  19. ^Gribkoff VK, Starrett JE, Dworetzky SI (Apr 2001). "Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium".The Neuroscientist.7(2): 166–77.doi:10.1177/107385840100700211.PMID11496927.S2CID8791803.
  20. ^Layne JJ, Nausch B, Olesen SP, Nelson MT (Feb 2010)."BK channel activation by NS11021 decreases excitability and contractility of urinary bladder smooth muscle".American Journal of Physiology. Regulatory, Integrative and Comparative Physiology.298(2): R378–84.doi:10.1152/ajpregu.00458.2009.PMC2828174.PMID19923353.
  21. ^Gribkoff VK, Winquist RJ (May 2005). "Voltage-gated cation channel modulators for the treatment of stroke".Expert Opinion on Investigational Drugs.14(5): 579–92.doi:10.1517/13543784.14.5.579.PMID15926865.S2CID10236998.
  22. ^Jensen BS (2002)."BMS-204352: a potassium channel opener developed for the treatment of stroke".CNS Drug Reviews.8(4): 353–60.doi:10.1111/j.1527-3458.2002.tb00233.x.PMC6741660.PMID12481191.
  23. ^Laumonnier F, Roger S, Guérin P, Molinari F, M'rad R, Cahard D, Belhadj A, Halayem M, Persico AM, Elia M, Romano V, Holbert S, Andres C, Chaabouni H, Colleaux L, Constant J, Le Guennec JY, Briault S (2006). "Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation".The American Journal of Psychiatry.163(9): 1622–1629.doi:10.1176/ajp.2006.163.9.1622.PMID16946189.S2CID25225269.
  24. ^Hébert B; Pietropaolo S; Même S; Laudier B; Laugeray A; Doisne N; Quartier A; Lefeuvre S; Got L; Cahard D; Laumonnier F;Crusio WE;Pichon J; Menuet A; Perche O; Briault S (2014)."Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule".Orphanet Journal of Rare Diseases.9:124.doi:10.1186/s13023-014-0124-6.PMC4237919.PMID25079250.

Further reading

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