SK channel

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Calcium-activated SK potassium channel
SK Channel.jpg
SK Channel
Identifiers
SymbolSK_channel
Pfam PF03530
InterPro IPR015449

SK channels (small conductance calcium-activated potassium channels) are a subfamily of Ca2+-activated K+ channels. [1] They are so called because of their small single channel conductance in the order of 10 pS. [2] SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. [3] SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory. [4]

Contents

Function

SK channels are expressed throughout the central nervous system. They are highly conserved in mammals as well as in other organisms such as Drosophila melanogaster and Caenorhabditis elegans . [5] SK channels are specifically involved in the medium afterhyperpolarizing potential (mAHP). They affect both the intrinsic excitability of neurons and synaptic transmission. They are also involved in calcium signaling. [6] SK channel activation can mediate neuroprotection in various models of cell death. [6] [7] [8] SK channels control action potential discharge frequency in hippocampal neurons, midbrain dopaminergic neurons, dorsal vagal neurons, sympathetic neurons, nucleus reticularis thalamic neurons, inferior olive neurons, spinal and hypoglossal motoneurons, mitral cells in the olfactory bulb, and cortical neurons. [3]

Structure

SK potassium channels share the same basic architecture with Shaker-like voltage-gated potassium channels. [9] Four subunits associate to form a tetramer. Each of the subunits has six transmembrane hydrophobic alpha helical domains (S1-S6). A loop between S5 and S6—called the P-loop—provides the pore-forming region that always faces the center of the channel. [10] Each of the subunits has six hydrophobic alpha helical domains that insert into the cell membrane. A loop between the fifth and sixth transmembrane domains forms the potassium ion selectivity filter. SK channels may assemble as homotetrameric channels or as heterotetrameric channels, consisting of more than one SK channel subtype. In addition, SK potassium channels are tightly associated with the protein calmodulin, which accounts for the calcium sensitivity of these channels. [9] [11] Calmodulin participates as a subunit of the channel itself, bound to the cytoplasmic C-terminus region of the peptide called the calmodulin binding domain (CaMBD). [12]

Additional association of the phosphorylating kinase CK2 and dephosphorylating phosphatase PP2A on the cytoplasmic face of the protein allow for enriched Ca2+-sensitivity—and thus—kinetics modulation. [13] CK2 serves to phosphorylate the SKCa-bound CaM at the T80 residue, rather than the channel helices themselves, to reduce calcium sensitivity. This may only be accomplished when the channel pore is closed. PP2A dephosphorylates this residue upon CK2 inhibition. [12] The selectivity filter of all SK channel subtypes—whether SK1, SK2, SK3, or SK4—is highly conserved and reflects the selectivity seen in any potassium channel, a GYGD amino acid residue sequence on the pore-forming loop. [14] These channels are considered to be voltage-independent, as they possess only two of seven positively charged amino acid residues that are typically seen in a prototypical voltage-gated potassium channel. [10]

Classification

The SK channel family contains 4 members – SK1, SK2, SK3, and SK4. SK4 is often referred to as IK (Intermediate conductance) due to its higher conductance 20 – 80 pS. [15]

ChannelGeneAliasesAssociated subunits
SK1 KCNN1 Kca2.1 calmodulin, PP2A, CK2
SK2 KCNN2 Kca2.2 calmodulin, PP2A, CK2
SK3 KCNN3 Kca2.3 calmodulin, PP2A, CK2
SK4 KCNN4 Kca3.1 calmodulin, PP2A, CK2

Gating mechanism

The SK channel gating mechanism is controlled by intracellular calcium levels. [5] Calcium enters the cell via voltage activated calcium channels as well as through NMDA receptors. [3] Calcium does not directly bind to the SK channel. Even in the absence of calcium, the SK channel binds to the C-lobe of the protein calmodulin (CaM). When the N-lobe binds calcium, it traps the S4-S5 linker on the intracellular subunit of the SK channel. When each of the four S4-S5 linkers are bound to the N-lobe of calmodulin, the SK channel changes conformation. Calmodulin pushes the S4-S5 linker to allow the expansion of the S6 bundle crossing, leading to opening of the pore. The idea that this transitions the channel from a tetramer of monomers to a folded dimer of dimers, which results in rotation of the CaM-binding domains is now abandoned, and the most recent observations are not compatible with the proposal that this rotation causes the mechanical opening of the channel gate. [5] The time constant of SK channel activation is approximately 5 ms. When calcium levels are depleted, the time constant for channel deactivation ranges from 15–60 ms. [16]

Blockers

All SK channels can be pharmacologically blocked by quaternary ammonium salts of a plant-derived neurotoxin bicuculline. [17] In addition, SK channels (SK1-SK3) but not SK4 (IK) are sensitive to blockade by the bee toxin apamin, [18] and the scorpion venoms tamapin and charybdotoxin (ChTx), all via competitive antagonism for access to the mouth of the pore formation. [19] All known blockers compete for roughly the same binding site, the pore, in all subtypes. This provides a physical blockage to the channel pore. [20] Since all blockers are universal to all three types of SK channels, there is an incredibly narrow therapeutic window that does not allow for blocking of a specific SK channel subtype. [13] Quaternary ammonium salts like bicuculline and tetraethylammonium (TEA) enter the pore via the selectivity filter by acting as a potassium mimic in the dehydration step of pore permeation. [20]

The following molecules are other toxins and organic compounds that also inhibit all three small SK channel subtypes to any (even minimal) degree: [13]

Modulators

Allosteric modulators of small SK channels work by changing the apparent calcium sensitivity of the channels. Examples include:


Chemical structure of SK ion channel modulators. SK channel modulators.png
Chemical structure of SK ion channel modulators.

Synaptic plasticity and long term potentiation

In dendritic spines, SK channels are directly coupled to NMDA receptors. In addition to being activated by calcium flow through voltage-gated calcium channels, SK channels can be activated by calcium flowing through NMDA receptors, which occurs after depolarization of the postsynaptic membrane. [12] Experiments using apamin have shown that specifically blocking SK channels can increase learning and long-term potentiation. In addition, brain-derived neurotrophic factor (BDNF) causes the down-regulation of SK channels, which facilitates long-term potentiation. Increasing SK channel activity has the opposite effect and serves to impair learning. [5] An increase in SK channel activity that occurs over time may be related to decreases in plasticity and memory that is seen with aging. [24]

Role in Parkinson's disease

The dysfunction of potassium channels, including SK channels, is thought to play a role in the pathogenesis of Parkinson's disease (PD), a progressive neurodegenerative disorder.

SK channel blockers control the firing rate (the number of action potentials produced by a neuron in a given time) and the firing pattern (the way action potentials are allocated throughout time) through their production of m-AHP. SK channel activators decrease the firing rate, neuron sensitivity to excitatory stimuli, mediating neuroprotection, whereas SK channel blockers increase the firing rate and sensitivity to excitatory stimuli. [25] This has important implications as to the function of dopaminergic neurons. [25] For example, the amount of dopamine released by midbrain dopaminergic neurons is much higher when the frequency of firing increases than when they fire at a constant rate.

SK channels are widely expressed in midbrain dopaminergic neurons. Multiple pharmacological techniques have been used to adjust SK affinity for calcium ions, thereby modulating the excitability of substantia nigra dopaminergic neurons. Blockage of SK channels in vivo increases the firing rate of substantia nigra cells, which increases the amount of dopamine released from the synaptic terminals. [25] When a large amount of dopamine accumulates in the cytosol, cell damage is induced due to the build-up of free radicals and damage to mitochondria. In addition, techniques have been used to modulate SK channels in order to alter the dopamine phenotype of neurons. After the loss of TH+ (tyrosine hydroxylase-positive) substantia nigra compacta (SNc) neurons due to Parkinson’s-induced neurodegeneration, the number of these neurons can partially recover via a cell phenotype "shift" from TH- (tyrosine hydroxylase-negative) to TH+. The number of TH+ neurons can be altered by SK channel modulation; to be specific, the infusion of SK agonists into substantia nigra increases the number of TH+ neurons, whereas the infusion of SK antagonist decreases the number of TH+ neurons. The reason for this relationship between SK channels and TH expression may be due to neuroprotection against dopamine toxicity. [25]

Two contradictory methods have been suggested as therapeutic options for the improvement of PD symptoms:

Inhibition of SK channels

Facilitation of SK channels

Related Research Articles

Substantia nigra Structure in the basal ganglia of the brain

The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.

Calmodulin

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

BK channel

BK channels (big potassium), are large conductance calcium-activated potassium channels, 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. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. 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.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. IPSP were first investigated in motorneurons by David P. C. Lloyd, John Eccles and Rodolfo Llinás in the 1950s and 1960s. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell to cell signalling. Inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors; this induces a change in the permeability of the postsynaptic neuronal membrane to particular ions. An electric current that changes the postsynaptic membrane potential to create a more negative postsynaptic potential is generated, i.e. the postsynaptic membrane potential becomes more negative than the resting membrane potential, and this is called hyperpolarisation. To generate an action potential, the postsynaptic membrane must depolarize—the membrane potential must reach a voltage threshold more positive than the resting membrane potential. Therefore, hyperpolarisation of the postsynaptic membrane makes it less likely for depolarisation to sufficiently occur to generate an action potential in the postsynaptic neurone.

Bicuculline

Bicuculline is a phthalide-isoquinoline compound that is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from Dicentra cucullaria, Adlumia fungosa, and several Corydalis species. Since it blocks the inhibitory action of GABA receptors, the action of bicuculline mimics epilepsy; it also causes convulsions. This property is utilized in laboratories across the world in the in vitro study of epilepsy, generally in hippocampal or cortical neurons in prepared brain slices from rodents. This compound is also routinely used to isolate glutamatergic receptor function.

Repolarization

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+-Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

Dopamine transporter

The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that Calcium levels inside of a cell could affect the permeability of potassium through that cell membrane. Then in 1970, Meech was the first to observe that intracellular calcium could trigger potassium currents. In humans they are divided into three subtypes: large conductance or BK channels, which have very high conductance which range from 100 to 300 pS, intermediate conductance or IK channels, with intermediate conductance ranging from 25 to 100 pS, and small conductance or SK channels with small conductances from 2-25 pS.

T-type calcium channels are low voltage activated calcium channels that become deinactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

SK3

SK3 also known as KCa2.3 is a protein that in humans is encoded by the KCNN3 gene.

Apamin Chemical compound

Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin (bee venom). Dry bee venom consists of 2–3% of apamin. Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system. Toxicity is caused by only a few amino acids, these are cysteine1, lysine4, arginine13, arginine14 and histidine18. These amino acids are involved in the binding of apamin to the Ca2+-activated K+ channel. Due to its specificity for SK channels, apamin is used as a drug in biomedical research to study the electrical properties of SK channels and their role in the afterhyperpolarizations occurring immediately following an action potential.

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

Calcium-activated potassium channel subunit alpha-1 also known as large conductance calcium-activated potassium channel, subfamily M, alpha member 1 (KCa1.1), or BK channel alpha subunit, is a voltage gated potassium channel encoded by the KCNMA1 gene and characterized by their large conductance of potassium ions (K+) through cell membranes.

KCNN4

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.

KCNB1

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

Ca<sub>v</sub>1.3

Calcium channel, voltage-dependent, L type, alpha 1D subunit is a protein that in humans is encoded by the CACNA1D gene. Cav1.3 channels belong to the Cav1 family, which form L-type calcium currents and are sensitive to selective inhibition by dihydropyridines (DHP).

KCNN2

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, also known as KCNN2, is a protein which in humans is encoded by the KCNN2 gene. KCNN2 is an ion channel protein also known as KCa2.2.

KCNN1

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1 , also known as KCNN1 is a human gene encoding the KCa2.1 protein.

Calmodulin binding domain

In molecular biology, calmodulin binding domain (CaMBD) is a protein domain found in small-conductance calcium-activated potassium channels (SK channels). These channels are independent of voltage and gated solely by intracellular Ca2+. They are heteromeric complexes that comprise pore-forming alpha-subunits and the Ca2+-binding protein calmodulin (CaM). CaM binds to the SK channel through the CaMBD, which is located in an intracellular region of the alpha-subunit immediately carboxy-terminal to the pore. Channel opening is triggered when Ca2+ binds the EF hands in the N-lobe of CaM. The structure of this domain complexed with CaM is known. This domain forms an elongated dimer with a CaM molecule bound at each end; each CaM wraps around three alpha-helices, two from one CaMBD subunit and one from the other.

D. James "Jim" Surmeier, an American neuroscientist and physiologist of note, is the Nathan Smith Davis Professor and Chair in the Department of Physiology at Northwestern University. His research is focussed on the cellular physiology and circuit properties of the basal ganglia in health and disease, primarily Parkinson's and Huntington's disease as well as pain.

References

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  3. 1 2 3 Faber ES, Sah P (October 2007). "Functions of SK channels in central neurons". Clinical and Experimental Pharmacology & Physiology. 34 (10): 1077–83. doi:10.1111/j.1440-1681.2007.04725.x. PMID   17714097. S2CID   5553791.
  4. ↑ Stackman RW, Hammond RS, Linardatos E, Gerlach A, Maylie J, Adelman JP, Tzounopoulos T (December 2002). "Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding". The Journal of Neuroscience. 22 (23): 10163–71. doi: 10.1523/JNEUROSCI.22-23-10163.2002 . PMC   6758766 . PMID   12451117.
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  7. ↑ Honrath B, Matschke L, Meyer T, Magerhans L, Perocchi F, Ganjam GK, et al. (May 2017). "SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake". Cell Death and Differentiation. 24 (5): 761–773. doi:10.1038/cdd.2017.2. PMC   5423111 . PMID   28282037.
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  11. ↑ Schumacher MA, Rivard AF, Bächinger HP, Adelman JP (April 2001). "Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin". Nature. 410 (6832): 1120–4. Bibcode:2001Natur.410.1120S. doi:10.1038/35074145. PMID   11323678. S2CID   205016620.
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  23. ↑ Hougaard C, Eriksen BL, Jørgensen S, Johansen TH, Dyhring T, Madsen LS, et al. (July 2007). "Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels". British Journal of Pharmacology. 151 (5): 655–65. doi:10.1038/sj.bjp.0707281. PMC   2014002 . PMID   17486140.
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