SK channel

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. 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. SK channel activation can mediate neuroprotection in various models of cell death. 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. This mechanism contributes to the loss of higher cognitive function during stress exposure == 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 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. 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 enriched Ca2+-sensitivity—and thus—kinetics modulation. 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. ==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 via competitive antagonism for access to the mouth of the pore formation. All known blockers compete for roughly the same binding site, the pore, in all subtypes. This provides a physical blockage to the channel pore. 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 small SK channel subtypes to any (even minimal) degree: • Dequalinium • d-Tubocurarine • UCL-1684 • UCL-1848 • Cyproheptadine • Fluoxetine, the active ingredient in Prozac • NS8593 • Scyllatoxin (Leiurotoxin-I) • Lei-Dab7 • N-methyl-laudanosine • N-Me-bicuculline • Pancuronium • Atracurium • 1-ethyl-1H-benzo[d]imidazol-2(3H)-on • 6,7-dichloro-3-(hydroxyimino)indolin-2-one • N-cyclohexyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine • (R)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazol-2-amine ==Modulators==

Allosteric modulators of small SK channels work by changing the apparent calcium sensitivity of the channels. Examples include: • Riluzole • Non-selective positive modulators of SK channels: EBIO (1-Ethyl-2-BenzimIdazolinOne), NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime) • SK-2 and SK-3 selective positive modulators : CyPPA (NS6277; Cyclohexyl-(2-(3,5-dimethyl-Pyrazol-1-yl)-6-methyl-Pyrimidin-4-yl)-Amine) ==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. == 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. 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+ (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. Two contradictory methods have been suggested as therapeutic options for the improvement of PD symptoms: Inhibition of SK channels • Inhibition of SK channels, to be specific 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. Facilitation of SK channels • 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. == References ==