BK channel

BK Channel Structure

Template:Infobox protein Template:Infobox protein Template:Infobox protein Template:Infobox protein family BK channels (big potassium), are large conductance calcium-activated potassium channels,<ref name="Zang">Template:Cite journal</ref> also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K⁺) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca²⁺ concentrations in the cell.<ref>Miller, C. (2000). Genome Biology, 1(4), reviews0004.1. https://dx.doi.org/10.1186/gb-2000-1-4-reviews0004</ref><ref>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</ref> BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability.<ref name="N'Gouemo_2011">Template:Cite journal</ref> BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many 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.

StructureEdit

Structurally, BK channels are homologous to voltage- and ligand-gated potassium channels, having a voltage sensor and pore as the membrane-spanning domain and a cytosolic domain for the binding of intracellular calcium and magnesium.<ref name="Lee_2010" /> Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function:

the voltage sensing domain (VSD) senses membrane potential across the membrane,
the cytosolic domain (senses calcium concentration, Template:Chem2 ions), and
the pore-gate domain (PGD) which opens and closes to regulate potassium permeation.

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).<ref name="Lee_2010">Template:Cite journal</ref> The voltage sensing domain and pore-gated domain are collectively referred as the membrane-spanning domains and are formed by transmembrane segments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primary voltage sensor.<ref name="Atkinson_1991">Template:Cite journal</ref>

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.<ref name="Lee_2010" /> Also unique to BK channels is an additional S0 segment, this segment is required for β subunit modulation.<ref name="Morrow_2006">Template:Cite journal</ref><ref name="Wallner_1996">Template:Cite journal</ref> and voltage sensitivity.<ref name="Koval_2007">Template:Cite journal</ref>

The Cytosolic domain is composed of two RCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinity Template:Chem2 binding sites: one in the RCK1 domain and the other in a region termed the Template:Chem2 bowl that consists of a series of Aspartic acid (Asp) residues that are located in the RCK2 domain. The Template:Chem2 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, and Glutamine residues in RCK1.<ref name="Lee_2010" /> In forming the Template:Chem2 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 Template:Chem2 ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity.<ref name="Lee_2010" /> Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrameric 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 for smooth muscle cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within the brain.<ref name="Lee_2010" /> The VSD associates with the PGD via three major interactions:

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

RegulationEdit

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 (Template:Chem2, Template:Chem2), PKC, The BK α-subunits assemble 1:1 with four different auxiliary types of β-subunits (β1, β2, β3 or β4).<ref name="Hermann_2015" />

Trafficking to and expression of BK channels in the plasma membrane has been found to be regulated by distinct splicing motifs located within the intracellular C-terminal RCK domains. In particular a splice variant that excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impacts physiology and pathophysiology.<ref name="Hermann_2015" />

BK channels in the vascular system are modulated by agents naturally produced in the body, such as angiotensin II (Ang II), high glucose or arachidonic acid (AA) which is modulated in diabetes by oxidative stress (ROS).<ref name="Hermann_2015" />

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.<ref name="Yang_2015">Template:Cite journal</ref>

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.<ref name="Yang_2015" />

Activation mechanismEdit

BK channels are synergistically activated through the binding of calcium and magnesium ions, but can also be activated via voltage dependence.<ref name="Hermann_2015" /> Template:Chem2 - dependent activation occurs when intracellular Template:Chem2 binds to two high affinity binding sites: one located in the C-terminus of the RCK2 domain (Template:Chem2 bowl), and the other located in the RCK1 domain.<ref name="Lee_2010" /> The binding site within the RCK1 domain has somewhat of a lower affinity for calcium than the Template:Chem2 bowl, but is responsible for a larger portion of the Template:Chem2 sensitivity.<ref name="Cui_2009">Template:Cite journal</ref> Voltage and calcium activate BK channels using two parallel mechanisms, with the voltage sensors and the Template:Chem2 bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. The Template:Chem2 bowl accelerates activation kinetics at low Template:Chem2 concentrations while RCK1 site influences both activation and deactivation kinetics.<ref name="Yang_2015" /> 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 Template:Chem2 binding site, which increases the affinity of Template:Chem2 binding.<ref name="Cui_2009" />

Magnesium-dependent activation of BK channels activates via a low-affinity metal binding site that is independent from Template:Chem2-dependent activation. The Template:Chem2 sensor activates BK channels by shifting the activation voltage to a more negative range. Template:Chem2 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 ligands. The CTD activates the BK channel when bound with intracellular Template:Chem2 to allow for interaction with the voltage sensor domain (VSD).<ref name="Yang_2015" /> Magnesium is predominantly coordinated by six oxygen atoms from the side chains of oxygen-containing residues, main chain carbonyl groups in proteins, or water molecules.<ref name="Cui_2009" /> D99 at the C-terminus of the S0-S1 loop and N172 in the S2-S3 loop contain side chain oxygens in the voltage sensor domain that are essential for Template:Chem2 binding. Much like the Template:Chem2-dependent activation model, Template:Chem2-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.<ref name="Cui_2009" /> This is also known as the Nudging model, in which Magnesium activates the channel by pushing the voltage sensor via electrostatic interactions and involves the interactions among side chains in different structural domains.<ref name="Lee_2010" /> Energy provided by voltage, Template:Chem2, and Template:Chem2 binding will propagate to the activation gate of BK channels to initiate ion conduction through the pore.<ref name="Lee_2010" />

Effects on the neuron, organ, body as a wholeEdit

Cellular levelEdit

BK channels help regulate both the firing of neurons and neurotransmitter release.<ref name="Yu_2016">Template:Cite journal</ref> This modulation of synaptic transmission and electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels.<ref name="Hermann_2015">Template:Cite journal</ref> The opening of these channels causes a drive towards the potassium equilibrium potential and thus play a role in speeding up the repolarization of action potentials.<ref name="Hermann_2015" /> This would effectively allow for more rapid stimulation.<ref name="Hermann_2015" /> There is also a role played in shaping the general repolarization of cells, and thus after hyperpolarization (AHP) of action potentials.<ref name="Bentzen_2014">Template:Cite journal</ref> The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus.<ref name="Bentzen_2014" /> It can also play a role in inhibiting the release of neurotransmitters.<ref name="Contet_2016">Template:Cite book</ref> There are many BK channels in Purkinje cells in the cerebellum, thus highlighting their role in motor coordination and function.<ref name="Bentzen_2014" /> Furthermore, BK channels play a role in modulating the activity of dendrites as well as astrocytes and microglia.<ref name="Contet_2016" /> They not only play a role in the CNS (central nervous system) but also in smooth muscle contractions, the secretion of endocrine cells, and the proliferation of cells.<ref name="Yu_2016" /> 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.<ref name="Hermann_2015" /> Therefore, these subunits can be targets for therapeutic treatments as BK channel activators.<ref name="Hermann_2015" /> There is further evidence that inhibiting BK channels would prevent the efflux of potassium and thus reduce the usage of ATP, in effect allowing for neuronal survival in low oxygen environments.<ref name="Hermann_2015" /> BK channels can also function as a neuronal protectant in terms such as limiting calcium entry into the cells through methionine oxidation.<ref name="Hermann_2015" />

Organ levelEdit

BK channels also play a role in hearing.<ref name="Bentzen_2014" /> This was found when the BK ɑ-subunit was knocked out in mice and progressive loss of cochlear hair cells, and thus hearing loss, was observed.<ref name="Bentzen_2014" /> BK channels are not only involved in hearing, but also circadian rhythms. Slo binding proteins (Slobs) can modulate BK channels as a function of circadian rhythms in neurons.<ref name="Hermann_2015" /> BK channels are expressed in the suprachiasmatic nucleus (SCN), which is characterized to influence the pathophysiology of sleep.<ref name="Bentzen_2014" /> BK channel openers can also have a protective effect on the cardiovascular system.<ref name="Hermann_2015" /> At a low concentration of calcium BK channels have a greater impact on vascular tone.<ref name="Hermann_2015" /> Furthermore, the signaling system of BK channels in the cardiovascular system have an influence on the functioning of coronary blood flow.<ref name="Hermann_2015" /> 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 of seizures in the temporal lobe.<ref name="Hermann_2015" />

Bodily function levelEdit

Mutations of BK channels, resulting in a lower amount of expression in mRNA, is more common in people who have mental disabilities (via hypofunction <ref name="Contet_2016" />), schizophrenia or autism.<ref name="Hermann_2015" /> Moreover, increased repolarization caused by BK channel mutations may lead to dependency of alcohol initiation of dyskinesias, epilepsy or paroxysmal movement disorders.<ref name="Hermann_2015" /> Not only are BK channels important in many cellular processes in the adult it also is crucial for proper nutrition supply to a developing fetus.<ref name="Hermann_2015" /> Thus, estrogen can cause an increase in the density of BK channels in the uterus.<ref name="Hermann_2015" /> However, increased expression of BK channels have been found in tumor cells, and this could influence future cancer therapy, discussed more in the pharmacology section.<ref name="Hermann_2015" /> 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.

PharmacologyEdit

Potential issuesEdit

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 gasotransmitters carbon monoxide,<ref name="pmid15664403">Template:Cite journal</ref><ref name="pmid18316727">Template:Cite journal</ref> nitric oxide, and hydrogen sulphide.<ref name="pmid19802723">Template:Cite journal</ref> Mutations in the proteins involved with BK channels or genes encoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as: epilepsy, cancer, diabetes, asthma, and hypertension.<ref name="Yu_2016" /> Specifically, β1 defect can increase blood pressure and hydrosaline retention in the kidney.<ref name="Yu_2016" /> Both loss of function and gain of function mutations have been found to be involved in disorders such as epilepsy and chronic pain.<ref name="Contet_2016" /> Furthermore, increases in BK channel activation, through gain-of-function mutants and amplification, has links to epilepsy and cancer.<ref name="Yu_2016" /> 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.<ref name="Bentzen_2014" /> It is known that BK channels do in some way influence the division of cells during replication, which when unregulated can lead to cancers and tumors.<ref name="Bentzen_2014" /> 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.<ref name="Bentzen_2014" /> Another reason why BK channel understanding is important involves its role in organ transplant surgery. This is due to the activation of BK channels influencing repolarization of the resting membrane potential.<ref name="Hermann_2015" /> Thus, understanding is crucial for safety in effective transplantation.

Current developmentsEdit

BK channels can be used as pharmacological targets for the treatment of several medical disorders including stroke<ref>Template:Cite journal</ref> and overactive bladder.<ref>Template:Cite journal</ref> There have been attempts to develop synthetic molecules targeting BK channels,<ref name="pmid15926865">Template:Cite journal</ref> however their efforts have proven largely ineffective thus far. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo.<ref name="pmid12481191">Template:Cite journal</ref> However, there have been some success from the agonist to BKCa channels, BMS-204352, in treating deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome.<ref name="pmid16946189">Template:Cite journal</ref><ref name="pmid25079250">Template:Cite journal</ref> BK channels also function as a blocker in ischemia and are a focus in investigating its use as a therapy for stroke.<ref name="Hermann_2015" />

Future directionsEdit

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 cognition enhancement, improved memory, and relieving depression.<ref name="Yu_2016" /> A behavioral response to alcohol is also modulated by BK channels,<ref name=" Hermann_2015" /> therefore further understanding of this relationship can aid treatment in patients who are 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.<ref name="Hermann_2015" /> Thus, the signaling system can be involved in treating hypertension and atherosclerosis<ref name="Hermann_2015" /> 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.<ref name="Bentzen_2014" /> 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.<ref name="N'Gouemo_2011" /> 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.

ReferencesEdit

Template:Reflist

External linksEdit

Template:MeshName
{{#invoke:citation/CS1|citation

|CitationClass=web }}

Template:Ion channels