KCNMA1
The domain structure of BK channels
Identifiers
Symbol	KCNMA1
Alt. symbols	SLO
NCBI gene	3778
HGNC	6284
OMIM	600150
RefSeq	NM_002247
UniProt	Q12791
Other data
Locus	Chr. 10q22
Search for Structures Swiss-model Domains InterPro

BK channels (big potassium), arelarge conductance calcium-activated potassium channels,^[1] and is also known asBKCa,^[2]Maxi-K,slo1,^[3] orKca1.1. BK channels arevoltage-gated potassium channels that 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.^[4][5] BK channels help regulate physiological processes, such ascircadian behavioral rhythms and neuronal excitability.^[6] BK channels are also involved in many processes in the body, as it is aubiquitous channel. They have atetrameric structure that is composed of atransmembrane domain,voltage sensing domain,potassium channel domain, and acytoplasmicC-terminal domain, with manyX-ray structures for reference. Their function is torepolarize the membrane potential by allowing for potassium to flow outward, in response to adepolarization or increase in calcium levels.

Structurally, BK channels are homologous tovoltage- andligand-gatedpotassium channels, having avoltage sensor and pore as themembrane-spanning domain and acytosolic domain for the binding of intracellularcalcium andmagnesium.^[7] Eachmonomer of the channel-forming alpha subunit is the product of theKCNMA1 gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function:

• Thevoltage sensing domain (VSD) sensesmembrane potential across the membrane,
• Thecytosolic domain (senses calcium concentration,Ca²⁺ ions), and
• The pore-gate domain (PGD) which opens and closes to regulatepotassiumpermeation.

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).^[7] The voltage sensing domain and pore-gated domain are collectively referred to as themembrane-spanning domains and are formed bytransmembrane segments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primaryvoltage sensor.^[8]

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.^[7] Also unique to BK channels is an additional S0 segment, this segment is required for β subunitmodulation.^[9][10] and voltage sensitivity.^[11]

The Cytosolic domain is composed of twoRCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinityCa²⁺binding sites:

• One in the RCK1 domain.
• One in a region termed theCa²⁺ 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,Asparagine residues in the cytosolic end of S2, andGlutamine residues in RCK1.^[7] 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 theMg²⁺ ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity.^[7] 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 cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within thebrain.^[7] 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.

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).^[12]

Trafficking to and expression of BK channels in theplasma membrane has been found to be regulated by distinct splicing motifs located within theintracellular C-terminal RCK domains. In particular asplice variant that excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impactsphysiology andpathophysiology.^[12]

BK channels in thevascular system are modulated by agents naturally produced in the body, such asangiotensin II (Ang II),high glucose orarachidonic acid (AA) which is modulated indiabetes byoxidative stress (ROS).^[12]

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.^[13]

Inhibition of BK channel activity byphosphorylation of 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 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.^[13]

BK channels aresynergistically activated through the binding ofcalcium andmagnesium ions, but can also be activated via voltage dependence.^[12]Ca²⁺ - dependent activation occurs when intracellularCa²⁺ binds to two high affinitybinding sites: one located in theC-terminus of the RCK2 domain (Ca²⁺ bowl), and the other located in the RCK1 domain.^[7] The binding site within the RCK1 domain has somewhat of a lower affinity for calcium than theCa²⁺ bowl, but is responsible for a larger portion of theCa²⁺ sensitivity.^[14] Voltage and calcium activate BK channels using two parallel mechanisms, with thevoltage sensors and theCa²⁺ bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. TheCa²⁺ bowl accelerates activation kinetics at lowCa²⁺ concentrations while RCK1 site influences both activation and deactivation kinetics.^[13] 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 change of the activation gate in channel opening is accompanied by aconformational change to theCa²⁺ binding site, which increases the affinity ofCa²⁺ binding.^[14]

Magnesium-dependent activation of BK channels activates via a low-affinity metal binding site that is independent fromCa²⁺-dependent activation. TheMg²⁺ 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 intracellularMg²⁺ to allow for interaction with thevoltage sensor domain (VSD).^[13] Magnesium is predominantly coordinated by sixoxygen atoms from the side chains of oxygen-containing residues, main chaincarbonyl groups inproteins, orwater molecules.^[14] D99 at the C-terminus of the S0-S1 loop andN172 in the S2-S3 loop contain side chain oxygens in the voltage sensor domain that are essential forMg²⁺ binding. Much like theCa²⁺-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.^[14] This is also known as the Nudging model, in which Magnesium activates the channel by pushing the voltage sensor viaelectrostatic interactions and involves the interactions amongside chains in different structural domains.^[7] Energy provided by voltage,Ca²⁺, andMg²⁺ binding will propagate to the activation gate of BK channels to initiateion conduction through the pore.^[7]

BK channels help regulate both the firing ofneurons andneurotransmitter release.^[15] This modulation ofsynaptic transmission and electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels.^[12] The opening of these channels causes a drive towards thepotassium equilibrium potential and thus play a role in speeding up therepolarization ofaction potentials.^[12] This would effectively allow for more rapid stimulation.^[12] There is also a role played in shaping the general repolarization of cells, and thusafter hyperpolarization (AHP) of action potentials.^[16] The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus.^[16] It can also play a role in inhibiting the release of neurotransmitters.^[17] There are many BK channels inPurkinje cells in thecerebellum, thus highlighting their role inmotor coordination and function.^[16] Furthermore, BK channels play a role in modulating the activity ofdendrites as well asastrocytes andmicroglia.^[17] 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.^[15] 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.^[12] Therefore, these subunits can be targets for therapeutic treatments as BK channel activators.^[12] 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.^[12] BK channels can also function as a neuronal protectant in terms such as limiting calcium entry into the cells throughmethionine oxidation.^[12]

BK channels also play a role inhearing.^[16] This was found when the BK ɑ-subunit was knocked out inmice and progressive loss of cochlear hair cells, and thus hearing loss, was observed.^[16] BK channels are not only involved in hearing, but alsocircadian rhythms. Slo binding proteins (Slobs) can modulate BK channels as a function ofcircadian rhythms in neurons.^[12] BK channels are expressed in thesuprachiasmatic nucleus (SCN), which is characterized to influence thepathophysiology of sleep.^[16] BK channel openers can also have a protective effect on thecardiovascular system.^[12] At a low concentration of calcium BK channels have a greater impact onvascular tone.^[12] Furthermore, the signaling system of BK channels in the cardiovascular system have an influence on the functioning ofcoronary blood flow.^[12] 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 ofseizures in thetemporal lobe.^[12]

Mutations of BK channels, resulting in a lower amount of expression inmRNA, is more common in people who have mental disabilities (via hypofunction^[17]),schizophrenia orautism.^[12] Moreover, increasedrepolarization caused by BK channelmutations may lead to dependency of alcohol initiation ofdyskinesias,epilepsy, orparoxysmal movement disorders.^[12] Not only are BK channels important in many cellular processes in the adult it also is crucial for proper nutrition supply to a developingfetus.^[12] Thus,estrogen can cause an increase in the density of BK channels in theuterus.^[12] However, increased expression of BK channels have been found intumor cells, and this could influence futurecancer therapy, discussed more in the pharmacology section.^[12] 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.

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,^[18][19] nitric oxide, and hydrogen sulphide.^[20] Mutations in the proteins involved with BK channels orgenes encoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as:epilepsy,cancer,diabetes,asthma, andhypertension.^[15] Specifically, β1 defect can increaseblood pressure and hydrosaline retention in thekidney.^[15] Both loss of function and gain of function mutations have been found to be involved in disorders such as epilepsy andchronic pain.^[17] Furthermore, increases in BK channel activation, throughgain-of-function mutants and amplification, has links to epilepsy and cancer.^[15] Moreover, BK channels play a role in tumors as well as cancers. In certain cancers gBK, a variant ion channel calledglioma BK channel, can be found.^[16] 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.^[16] 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.^[16] Another reason why BK channel understanding is important involves its role inorgan transplant surgery. This is due to the activation of BK channels influencing repolarization of theresting membrane potential.^[12] Thus, understanding is crucial for safety in effective transplantation.

BK channels can be used aspharmacological targets for the treatment of several medical disorders includingstroke^[21] andoveractive bladder.^[22] There have been attempts to develop synthetic molecules targeting BK channels,^[23] 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.^[24] However, there have been some success from theagonist to BKCa channels, BMS-204352, in treating deficits observed inFmr1knockout mice, a model ofFragile X syndrome.^[25][26] BK channels also function as a blocker inischemia and are a focus in investigating its use as a therapy for stroke.^[12]

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 incognition enhancement, improvedmemory, and relievingdepression.^[15] A behavioral response to alcohol is also modulated by BK channels,^[12] therefore further understanding of this relationship can aid treatment in patients who arealcoholics.Oxidative stress on BK channels can lead to the negative impairments of lowering blood pressure through cardiovascular relaxation have on both aging and disease.^[12] Thus, the signaling system can be involved in treatinghypertension andatherosclerosis^[12] 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.^[16] 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-excitability of neurons, which BK channels have a large impact on controlling hyperexcitability.^[6] 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.

• Calcium-activated potassium channel subunit alpha-1
• Calcium-activated potassium channel
• Voltage-gated potassium channel

• BK+Channels at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• "Calcium-Activated Potassium Channels".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2012-09-02. Retrieved2012-08-20.

• Genes on human chromosome 10
• Genes on human chromosome 5
• Genes on human chromosome 3
• Genes on human chromosome 22
• Genes on human chromosome 12
• Potassium channels
• Electrophysiology

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