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SK channels (Small conductance calcium-activated potassium channels) are a subfamily of Ca2+-activated K+ channels. They are so called because of their small single channel conductance, ~10 pS. 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. Their activation limits the firing frequency of action potentials and are important for regulating afterhyperpolarization in central neurons and other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions into the extracellular space, along a concentration gradient. Hyperpolarization causes the voltage across a membrane to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in memory and learning.

Structure
SK potassium channels share the same basic architecture with Shaker-like voltage-gated potassium channels. 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. Each of the subunits has six hydrophobic alpha helical domains which insert into the cell membrane. A loop between the fifth and sixth transmembrane domain 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. 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). Additional association of the phosphorylating kinase CK2 and dephosphorylating phosphatase PP2A on the cytoplasmic face of the protein allow for additional Ca2+-sensitivity—and thus—kinetics modulation. 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. 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. 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.

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.

Gating Mechanism
The SK channel gating mechanism is controlled by intracellular calcium levels. Calcium enters the cell via voltage activated calcium channels as well as through NMDA receptors. Calcium does not directly bind to the SK channel. Calcium binds to the protein calmodulin (CaM). When bound to calcium, CaM binds to the CaM-binding domain on the intracellular subunit of the SK channel. When each of the four CaM-binding domain subunits is bound to calmodulin, the SK channel changes confirmation. This transitions the channel from a tetramer of monomers to a folded dimer of dimers which results in rotation of the CaM binding domains. This rotation causes the mechanical opening of the channel gate. Calcium enters the cell via voltage activated calcium channels as well as through NMDA receptors. The time constant of SK channel activation is approximately 5ms. When calcium levels are depleted, the time constant for channel deactivation ranges from 15-60ms.

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 C. elegans. SK channels are specifically involved in the medium afterhyperpolarizing potential (mAHP). They affect both the intrinsic excitability of neurons and synaptic transmission. SK channels control action potential discharge frequency in hippocampal neurons, midbrain dopaminergic neurons, dorsal vagal neurons, sympathetic neurons, nucleus reticularis thalmic neurons, inferior olive neurons, spinal and hypoglossal motoneurons, mitrial cells in the olfactory bulb, and cortical neurons.

Blockers
All SK channels can be pharmacologically blocked by quaternary ammonium salts of a plant-derived neurotoxin bicuculline. In addition, SK channels (SK1-SK3) but not SK4 (IK) are sensitive to blockade by the bee toxin apamin, and the scorpion venoms tamapin and charybdotoxin (ChTx). All known blockers compete for roughly the same binding site, the pore, in all subtypes. This provides a physical blockage to the channel pore. Since all blockers are universal to all three types of SK channels, this provides an incredibly narrow therapeutic window that does not allow for blocking of a specific SK channel subtype. 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.

The following molecules are other toxins and organic compounds that also inhibit all three SK channel subtypes to any (even minimal) degree:
 * Dequalinium
 * d-Turbocuranine
 * UCl-1684
 * UCL-1848
 * Cyproheptadine
 * Fluoxetine, the active ingredient in Prozac
 * NS8593
 * Scyllatoxin (Leiurotoxin-I)
 * Lei-Dab7

Modulators
Allosteric modulators of SK channels work by changing the apparent calcium sensitivity of the channels. Examples include:
 * Non selective positive modulators of SK channels: EBIO (1-Ethyl-2-BenzimIdazolinOne), NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime)
 * SK-3 selective positive modulators : CyPPA (NS6277; Cyclohexyl-(2-(3,5-dimethyl-Pyrazol-1-yl)-6-methyl-Pyrimidin-4-yl)-Amine)



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 and neuron sensitivity to excitatory stimuli, whereas SK channel blockers increase the firing rate and sensitivity to excitatory stimuli. This has important implications as to the function of dopaminergic neurons. 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. 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+ 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- to TH+. The number of TH+ neurons can be altered by SK channel modulation – specifically, the infusion of SK agonists into substantia nigra increases the number of TH+ neurons whereas the infusion of SK anatagonist 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.

Based on the two opposing roles of SK channels in the pathogenesis of PD, two contradictory methods have been suggested as therapeutic options for the improvement of PD symptoms: Inhibition of SK channels Facilitation of SK channels
 * Inhibition of SK channels, specifically the blockage of SK3 channels, increases the frequency of firing in dopaminergic neurons, thereby increasing the release of dopamine. It is therefore thought that the application of SK3 channels blockers in PD patients may alleviate short-term motor symptoms.
 * However, inhibition also results in a decreased number of TH+ substantia nigra compacta (SNc) neurons in the cell which results in a decrease in dopamine synthesis over the long term.
 * Enhancing the function of SK channels increases the number of TH+ substantia nigra compacta (SNc) neurons in the cell, thereby maintaining dopamine synthesis over the long term.
 * However, the facilitation of SK channels decreases the firing frequency in dopaminergic neurons over the short term.