Channelpedia

SK

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Introduction

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]

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Gene

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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Structure

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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Expression and Distribution

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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CNS Sub-cellular Distribution

SK1

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

SK2

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

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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Function

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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Interaction

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].

Apamin
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].

Neurotransmitters
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-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]

References

320

Cai X et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration.
Neuron, 2004 Oct 14 , 44 (351-64).

1099

Köhler M et al. Small-conductance, calcium-activated potassium channels from mammalian brain.
Science, 1996 Sep 20 , 273 (1709-14).

1100

Vergara C et al. Calcium-activated potassium channels.
Curr. Opin. Neurobiol., 1998 Jun , 8 (321-9).

1107

Faber ES et al. Functions of SK channels in central neurons.
Clin. Exp. Pharmacol. Physiol., 2007 Oct , 34 (1077-83).

1110

Ishii TM et al. A human intermediate conductance calcium-activated potassium channel.
Proc. Natl. Acad. Sci. U.S.A., 1997 Oct 14 , 94 (11651-6).

1111

Lee WS et al. Small conductance Ca2+-activated K+ channels and calmodulin: cell surface expression and gating.
J. Biol. Chem., 2003 Jul 11 , 278 (25940-6).

1112

Maylie J et al. Small conductance Ca2+-activated K+ channels and calmodulin.
J. Physiol. (Lond.), 2004 Jan 15 , 554 (255-61).

1113

Faber ES Functions and modulation of neuronal SK channels.
Cell Biochem. Biophys., 2009 , 55 (127-39).

1116

Bertram EH Temporal lobe epilepsy: where do the seizures really begin?
Epilepsy Behav, 2009 Jan , 14 Suppl 1 (32-7).

1118

Ermolinsky B et al. Deficit of Kcnma1 mRNA expression in the dentate gyrus of epileptic rats.
Neuroreport, 2008 Aug 27 , 19 (1291-4).

1120

Pacheco Otalora LF et al. Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy.
Brain Res., 2008 Mar 20 , 1200 (116-31).

1121

Sheehan JJ et al. Anticonvulsant effects of the BK-channel antagonist paxilline.
Epilepsia, 2009 Apr , 50 (711-20).

1122

Wang B et al. Mechanism of increased BK channel activation from a channel mutation that causes epilepsy.
J. Gen. Physiol., 2009 Mar , 133 (283-94).

1454

Kuiper EF et al. K(Ca)2 and k(ca)3 channels in learning and memory processes, and neurodegeneration.
Front Pharmacol, 2012 , 3 (107).

1459

Wulff H et al. K+ channel modulators for the treatment of neurological disorders and autoimmune diseases.
Chem. Rev., 2008 May , 108 (1744-73).

1480

Allen D et al. The SK2-long isoform directs synaptic localization and function of SK2-containing channels.
Nat. Neurosci., 2011 Jun , 14 (744-9).

1483

Deardorff AS et al. Expression of postsynaptic Ca2+-activated K+ (SK) channels at C-bouton synapses in mammalian lumbar -motoneurons.
J. Physiol. (Lond.), 2013 Feb 15 , 591 (875-97).

1484

Lin MT et al. SK2 channel plasticity contributes to LTP at Schaffer collateral-CA1 synapses.
Nat. Neurosci., 2008 Feb , 11 (170-7).

1486

Maas AJ et al. The effect of apamin on the smooth muscle cells of the guinea-pig taenia coli.
Eur. J. Pharmacol., 1979 Sep 15 , 58 (151-6).

1487

Gandolfo G et al. Sleep cycle disturbances induced by apamin, a selective blocker of Ca(2+)-activated K+ channels.
Brain Res., 1996 Oct 14 , 736 (344-7).

1488

McKay BM et al. Increasing SK2 channel activity impairs associative learning.
J. Neurophysiol., 2012 Aug 1 , 108 (863-70).

1492

N'Gouemo P Targeting BK (big potassium) channels in epilepsy.
Expert Opin. Ther. Targets, 2011 Nov , 15 (1283-95).

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