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Slow conductance calcium-activated potassium channels (also known as SK, KCa2 family) are potassium selective, voltage-independent, and activated by sub-micromolar concentrations of calcium through constitutively associated to calmodulin [542]. Three genes encode for the highly homologous mammalian SK channels have been cloned: SK1 (KCa2.1), SK2 (KCa2.2) and SK3 (KCa2.3) [1099]. They are selectively blocked by apamin and play are powerful modulators of electrical excitability by acting in close proximity of their Ca2+ sources to locally modulate membrane currents playing a fundamental role in all excitable cells. [1107] [1108] [1113]

They are expressed in the nervous system and in various other organs, including heart, liver and muscle, and cell types – such as endothelial cells and lymphocytes – where they often share their functions with KCa3.1. Like the other members of the family, they can co-localize with specific Ca2+ sources in a cell type-specific manner. [1458]



SK channel family contains 4 members – SK1 (KCa2.1.), SK2 (KCa2.2.), SK3 (KCa2.3.) and SK4 (KCa3.1 considered as intermediate conductance channel), which are expressed by different genes i.e. Kcnn1, Kcnn2, Kcnn3 and Kcnn4 respectively (Wulff et al., 2007 [1109]).





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SK channels are powerful modulators of electrical excitability and exert profound physiological effects both within and outside the nervous system. SK2 channels are potently blocked by a number of compounds containing two permanently charged or protonatable nitrogens and are activated by several relatively simple heterocyclic molecules. In contrast to SK blockers, which in general increase neuronal excitability, channel activators reduce excitability and have therefore been proposed for the treatment of CNS disorders that are characterized by hyperexcitability (See Figure 7 in Wulff and Zhorov 2008 [1459].

Native SK channels may be pharmacologically classified on the basis of their sensitivity to the bee venom peptide toxin apamin and their pharmacological differences has been usedto distinguish the contribution of the various SK channels in different physiological contexts [1100] [1459] [1481] [1109]:
-SK2 is highly sensitive to apamin, being half-blocked by 60pM.
-SK1 are not affected by 100nM apamin.
-SK3 channels are intermediate, with a Kd of -1 nM.

NMDA receptors SK2 channels are functionally coupled with NMDA receptors in CA1 spines such that their activity modulates the shape of excitatory postsynaptic potentials and increases the threshold for induction of LTP [1484].

Calmodulin Calcium independent interactions with calmodulin are required for surface expression of SK channels, whereas the constitutive association between the two channel subunits is not an essential requirement for gating. [1111][1112].

Glutamate receptors
mGluR regulate hippocampal CA1 pyramidal neuron excitability via activation of SK channels through regulation of intracellular calcium waves [1485].

Slow hyperpolarizing effects observed after stimulation of adrenergic, cholinergic, or purinergic pathways in smooth muscles of the gastrointestinal tract were caused by such an increase in K+ permeability as detected by the use of apamin [1486].

1-EBIO (1-Ethyl-2-benzimidazolinone) is a SK channel opener. [1115]

For further information about the pharmacology of recombinantly expressed SK channles see Table 1 in Pedarzani and Stocker 2008. [1481]



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SK channels consist of heterotetrameric subunit assembly of four identical subunits that associate to form a symmetric tetramer SK channels [1110]. Each of the subunits have six transmembrane segments (S1-S6) and intracellular N- and C-termini.4 However, SK2 channels only contain two positively charged amino acids in the S4 segment and are therefore insensitive to changes in membrane voltage. [1459]

Crystallographic studies suggest that SK channels gate as a dimer-of-dimers, and that the physical gate of SK channels resides at or near the selectivity filter of the channels. In addition, Ca(2+)-independent interactions between the SK channel alpha subunits and calmoduline are necessary for proper membrane trafficking. [1112]

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SK1 is frequently associated with neuronal fibers and only occasionally detected in neuronal somata. [1479]


In most brain regions, SK2 immunostaining is restricted to the plasma membrane of neuronal somata of defined fiber tracts. However, in some brain regions like the basolateral amygdala or the medial habenula, a more diffuse staining pattern is observed and it is unable to clearly assign the origin of immunostaining to defined neuronal compartments. It is also asscociated with both neuronal somata and fibers.
SK2 channels are expressed in the PSD of dendritic spines on CA1 pyramidal neurons [1479] and some results suggest that protein SK2-L may play a role in the subcellular localization of native SK2-containing channels [1480].


SK3 channel expression is punctate in nature and largely confined to varicose fibers, which likely represent subcellular compartments of high synaptic. Only occasionally, somatic immunostaining was observed like in the locus coeruleus or in tegmental nuclei. [1479]

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Central nervous system

SK channels are widely expressed in the central nervous system thereby potentially contributing to neuronal excitability control and they are critical regulators of neuronal excitability in hippocampus [1106]). For further information about SK channels expression see table 1 Densities of immunoreactivity for SK1, SK2, and SK3 proteins in various compartments of the mouse central nervous system in Sailer et al., 2006 [1479]).

SK1 is expressed, from highest to lowest levels in: amígdala, hippocampus, caudate nucleus, cerebellum , thalamus, substantia nigra, spinal cord and pituitary gland. [539]

SK2 channel labeling is strongest in the CA1–CA2 stratum radiatum and stratum oriens [1479]. It is also expressed in amígdala, corpus callosum, thalamus, caudate nucleus, and substantia nigra. [539] SK1 and SK2 are often expressed in the same neurons, predominantly in the neocortex, hippocampal formation, cerebellum, and thalamus [1479]).

SK3 is primarily expressed in subcortical regions , substantia nigra, amygdala, caudate nucleus, thalamus, hippocampus, ventral tegmental area, cerebellum, corpus callosum and spinal cord [1459], [539].

For further information about the expression of SK in CNS and their function see Pedarzani and Stocker 2008. [1481]

Perpheral tissue [1482], [539]

SK1 is found in testis, ovary and aorta and in several pathological conditions such oligodendroglioma, glioblastoma and gastric tumour.

SK2 channels are present in the adrenal glands, heart, kidneys, liver, prostate, and urinary bladder. Also in melanoma, germ cell tumour, and oligodendroglioma.

SK3 shows distinctive distribution to the small intestine, rectum, omentum, myometrium, skeletal muscles, lymphocytes, prostate, heart, kidney, pituitary gland, liver, pancreas and colon.

Rat, mouse and cat spinal cord show a differential and overlapping expression of SK2 and SK3 isoforms across specific types of α-motoneurons. In rodents, SK2 is expressed in all α-motoneurons whereas SK3 is expressed preferentially in small-diameter ones; in cats, SK3 is expressed in all α-motoneurons. [1483]

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SK channels are potassium selective and activated by an increase in the level of intracellular calcium, such as occurs during an action potential causing membrane hyperpolarization and inhibiting cell firing. The intracellular calcium increase evoked by action potential firing decays slowly, allowing SK channel activation to generate a long-lasting hyperpolarization, termed the slow afterhyperpolarization (sAHP). The sAHP limits the firing frequency of repetitive action potentials. This spike-frequency adaptation protects the cell from the deleterious effects of continuous, tetanic activity and is essential for normal neurotransmission. [1100] [1099] These channels are subject to regulation by hosphorylation/dephosphorylation events [27], and heterotetramers can form. [1458]

In general, SK channels participate in [1454]:
-Neurotransmission in gastrointestinal smooth muscles
-Vascular relaxation
-Regulation of local blood flow after stroke
-Learning and memory (for further information about the role of KCa channels in plasticity see Figure 1 in Kuiper et al. 2012 [1454].The modulation of SK channels is an important cellular mechanism for associative learning and further support postburst AHP reductions in hippocampal pyramidal neurons as a biomarker of successful learning [1488].

Apamin-sensitive SK channels have been implicated in several important physiological processes.
-CNS: the application of apamin to the sensory motor portion of the inferior colliculus caused seizure activity [1492].
-Intracerebroventricular injections of apamin disturbed the circadian cycle and disrupted normal sleep patterns [1487].

Therefore, alterations on SK channels are related with: epilepsy, ataxia and disorders of the dopaminergic system [1481] [1116] [1117] [1118] [1119] [1120] [1121] [1122]. Recently, it has been found that SK3 channels present in microglia, are activated by aggregated forms of Aβ, implicating SK channels in the developement of Alzheimer disease [1493].

There is an enhancement of nucleus accumbens (NAcb) core action potential firing ex vivo after protracted abstinence from alcohol. Thus, decreased NAcb core SK currents and increased excitability represents a critical mechanism that facilitates motivation to seek alcohol after abstinence. [1489]

Mouse models:
Kcnc2-/- [1490]
SK3T/T [1491]
SK2-/- [1114]







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