SK2

Description: potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2
Gene: Kcnn2
Alias: SK2, hSK2, SKCA2, KCa2.2, Kcnn2

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Introduction

Ca2+-activated K+ channels are activated by rises in intracellular Ca2+. The KCa potassium channel family includes at least three subfamilies, KCa1–3 [539]. Channels containing the KCa1.1 alpha-subunit (BK channels) have large single channel conductance and are maximally activated by micromolar concentrations of intracellular free calcium and concurrent depolarization. Their kinetic and pharmacological properties are modified upon assembly with membrane standing beta-subunits [540]. The KCa2 subfamily of small conductance Ca2+-activated K+ channels, also known as SK channels, has three closely related members SK1 (KCa2.1), SK2 (KCa2.2), and SK3 (KCa2.3), which are characterized by a small single channel conductance. The IK channel (KCa3.1) shows an intermediate single channel conductance. Both SK and IK channels are voltage-independent and activated by submicromolar concentrations of intracellular free Ca2+. The gating of SK and IK channels is induced upon Ca2+ binding to calmodulin, which is constitutively bound to each channel subunit. Ca2+ binding to calmodulin induces a conformational change, which leads to the opening of these channels [541], [542], [543].

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Gene

Species	NCBI gene ID	Chromosome	Position
Human	3781	5	440518
Mouse	140492	18	417200
Rat	54262	18	440381

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_021614.4	2760
Mouse	NM_001312905.2	3692
Rat	NM_001309404.1	2069

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	Q9H2S1	579
Mouse	P58390	839
Rat	P70604	580

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NR_174097.1

2341

transcript variant 3

NR_103458.2

1578

transcript variant 4

NM_001372233.1

3822

NP_001359162.1

857

transcript variant 5

isoform c

NM_021614.4

2760

NP_067627.3

791

transcript variant 1

isoform a

NM_170775.3

1472

NP_740721.1

231

transcript variant 2

isoform b

Predicted

XM_047417166.1

4635

XP_047273122.1

847

transcript variant X2

isoform X2

XM_011543389.2

3753

XP_011541691.1

857

transcript variant X1

isoform X1

XM_017009457.2

1157

XP_016864946.1

275

transcript variant X3

isoform X3

XM_054352563.1

4639

XP_054208538.1

848

transcript variant X2

isoform X2

XM_054352562.1

3756

XP_054208537.1

858

transcript variant X1

isoform X1

XM_054352564.1

3224

XP_054208539.1

275

transcript variant X4

isoform X3

Known

NM_001312905.2

3692

NP_001299834.1

849

transcript variant 1

isoform SK2-L

NM_080465.2

2046

NP_536713.1

574

transcript variant 2

isoform SK2-S

Predicted

XR_004939835.1

3042

transcript variant X3

XR_004939836.1

2514

transcript variant X4

XM_036160982.1

4737

XP_036016875.1

842

transcript variant X2

isoform X2

XM_030250331.2

3793

XP_030106191.1

852

transcript variant X1

isoform X1

XM_036160983.1

1252

XP_036016876.1

231

transcript variant X5

isoform X3

Known

NM_001309404.1

2069

NP_001296333.1

583

transcript variant 1

isoform 1

NM_019314.2

2060

NP_062187.1

580

transcript variant 2

isoform 2

Predicted

XM_039097046.1

4550

XP_038952974.1

997

transcript variant X1

isoform X1

XM_039097049.1

3849

XP_038952977.1

811

transcript variant X5

isoform X5

XM_006254683.4

3699

XP_006254745.1

858

transcript variant X2

isoform X2

XM_039097047.1

3957

XP_038952975.1

848

transcript variant X4

isoform X4

XM_017601013.2

3687

XP_017456502.1

855

transcript variant X3

isoform X3

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Post-Translational Modifications

PTM

Position

Type

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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]

SK2 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	6063.37	source
Mouse	11927.49	source
Rat	8777.62	source

Methodology for AlphaFold size prediction and disclaimer are available here

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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]).

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]).

SK channels, predominantly of the SK2 type, have been identified in sensory systems such as the retina [545] and the cochlear inner and outer hair cells [546]. SK channels have also been described in heart [546], liver [547], skeletal muscle [548], [147], and visceral smooth muscle [549].

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CNS Sub-cellular Distribution

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].

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Function

The SK channel-mediated current regulates membrane excitability, increases the precision of neuronal firing [550], and modulates synaptic plasticity by regulating excitatory synaptic transmission in the amygdala [551] and the hippocampus [552]. Inhibition of SK channels facilitates hippocampal independent [553] as well as dependent learning [554] and improves memory performance [553].

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Interaction

Apamin

The bee venom toxin apamin inhibits exclusively the three cloned SK channel subtypes (SK1, SK2, and SK3) with different affinity, highest for SK2, lowest for SK1, and intermediate for SK3 channels. [141]

Methyl-laudanosine

The alkaloid methyl-laudanosine blocks SK1, SK2 and SK3 currents with equal potency, IK currents were unaffected. [143]

References

141

Nolting A et al. An amino acid outside the pore region influences apamin sensitivity in small conductance Ca2+-activated K+ channels.
J. Biol. Chem., 2007 Feb 9 , 282 (3478-86).

142

Villalobos C et al. SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons.
J. Neurosci., 2004 Apr 7 , 24 (3537-42).

143

Scuvée-Moreau J et al. Electrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slices.
Br. J. Pharmacol., 2004 Nov , 143 (753-64).

144

D'Hoedt D et al. Domain analysis of the calcium-activated potassium channel SK1 from rat brain. Functional expression and toxin sensitivity.
J. Biol. Chem., 2004 Mar 26 , 279 (12088-92).

145

Monaghan AS et al. The SK3 subunit of small conductance Ca2+-activated K+ channels interacts with both SK1 and SK2 subunits in a heterologous expression system.
J. Biol. Chem., 2004 Jan 9 , 279 (1003-9).

146

Benton DC et al. Small conductance Ca2+-activated K+ channels formed by the expression of rat SK1 and SK2 genes in HEK 293 cells.
J. Physiol. (Lond.), 2003 Nov 15 , 553 (13-9).

147

Ro S et al. Molecular properties of small-conductance Ca2+-activated K+ channels expressed in murine colonic smooth muscle.
Am. J. Physiol. Gastrointest. Liver Physiol., 2001 Oct , 281 (G964-73).

149

Kong JH et al. Expression of the SK2 calcium-activated potassium channel is required for cholinergic function in mouse cochlear hair cells.
J. Physiol. (Lond.), 2008 Nov 15 , 586 (5471-85).

150

Bruening-Wright A et al. Evidence for a deep pore activation gate in small conductance Ca2+-activated K+ channels.
J. Gen. Physiol., 2007 Dec , 130 (601-10).

151

Johnson SL et al. Genetic deletion of SK2 channels in mouse inner hair cells prevents the developmental linearization in the Ca2+ dependence of exocytosis.
J. Physiol. (Lond.), 2007 Sep 1 , 583 (631-46).

152

Hammond RS et al. Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity.
J. Neurosci., 2006 Feb 8 , 26 (1844-53).

153

Nie L et al. Cloning and expression of a small-conductance Ca(2+)-activated K+ channel from the mouse cochlea: coexpression with alpha9/alpha10 acetylcholine receptors.
J. Neurophysiol., 2004 Apr , 91 (1536-44).

539

Wei AD et al. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels.
Pharmacol. Rev., 2005 Dec , 57 (463-72).

540

Orio P et al. New disguises for an old channel: MaxiK channel beta-subunits.
News Physiol. Sci., 2002 Aug , 17 (156-61).

541

Fanger CM et al. Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1.
J. Biol. Chem., 1999 Feb 26 , 274 (5746-54).

542

Xia XM et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels.
Nature, 1998 Oct 1 , 395 (503-7).

543

Schumacher MA et al. Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin.
Nature, 2001 Apr 26 , 410 (1120-4).

544

Stocker M et al. Differential distribution of three Ca(2+)-activated K(+) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system.
Mol. Cell. Neurosci., 2000 May , 15 (476-93).

545

Klöcker N et al. Developmental expression of the small-conductance Ca(2+)-activated potassium channel SK2 in the rat retina.
Mol. Cell. Neurosci., 2001 Mar , 17 (514-20).

546

Glowatzki E et al. Cholinergic synaptic inhibition of inner hair cells in the neonatal mammalian cochlea.
Science, 2000 Jun 30 , 288 (2366-8).

547

Schetz JA et al. Pharmacology of the high-affinity apamin receptor in rabbit heart.
Cardiovasc. Res., 1995 Nov , 30 (755-62).

548

Hugues M et al. The Ca2+-dependent slow K+ conductance in cultured rat muscle cells: characterization with apamin.
EMBO J., 1982 , 1 (1039-42).

549

Banks BE et al. Apamin blocks certain neurotransmitter-induced increases in potassium permeability.
Nature, 1979 Nov 22 , 282 (415-7).

550

Stocker M et al. An apamin-sensitive Ca2+-activated K+ current in hippocampal pyramidal neurons.
Proc. Natl. Acad. Sci. U.S.A., 1999 Apr 13 , 96 (4662-7).

551

Faber ES et al. SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala.
Nat. Neurosci., 2005 May , 8 (635-41).

552

Ngo-Anh TJ et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines.
Nat. Neurosci., 2005 May , 8 (642-9).

553

Fournier C et al. Apamin improves reference memory but not procedural memory in rats by blocking small conductance Ca(2+)-activated K(+) channels in an olfactory discrimination task.
Behav. Brain Res., 2001 Jun , 121 (81-93).

554

Stackman RW et al. Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding.
J. Neurosci., 2002 Dec 1 , 22 (10163-71).

1106

Oliveira MS et al. Altered expression and function of small-conductance (SK) Ca(2+)-activated K+ channels in pilocarpine-treated epileptic rats.
Brain Res., 2010 Aug 12 , 1348 (187-99).

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).

1112

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

1459

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

1479

Sailer CA et al. Comparative immunohistochemical distribution of three small-conductance Ca2+-activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain.
Mol. Cell. Neurosci., 2004 Jul , 26 (458-69).

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).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/66/ , accessed on 2024 Apr 25

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