SK1

Description: potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1
Gene: Kcnn1
Alias: SK1, kcnn1, KCa2.1

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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	3780	19	48795
Mouse	84036	8	22533
Rat	54261	16	22922

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_002248.5	3633
Mouse	NM_001363407.1	3270
Rat	NM_019313.1	1611

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	Q92952	543
Mouse	Q9EQR3	537
Rat	P70606	536

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NR_170373.1

3587

transcript variant 6

NR_170374.1

3578

transcript variant 7

NM_002248.5

3633

NP_002239.2

543

transcript variant 1

isoform 1

NM_001386976.1

3604

NP_001373905.1

546

transcript variant 4

isoform 2

NM_001386975.1

3612

NP_001373904.1

546

transcript variant 3

isoform 2

NM_001386974.1

3603

NP_001373903.1

543

transcript variant 2

isoform 1

NM_001386977.1

3594

NP_001373906.1

540

transcript variant 5

isoform 3

Predicted

XM_011528004.2

3603

XP_011526306.1

626

transcript variant X1

isoform X1

XM_054320942.1

3603

XP_054176917.1

626

transcript variant X1

isoform X1

Known

NM_001363407.1

3270

NP_001350336.1

538

transcript variant 1

isoform a

NM_001363408.1

2918

NP_001350337.1

535

transcript variant 3

isoform b

NM_032397.3

2927

NP_115773.2

538

transcript variant 2

isoform a

Predicted

XR_003947357.2

2808

transcript variant X8

XR_870467.3

2919

transcript variant X7

XR_379049.3

2928

transcript variant X6

XM_030243866.1

5212

XP_030099726.1

538

transcript variant X4

isoform X3

XM_030243865.1

5289

XP_030099725.1

538

transcript variant X3

isoform X3

XM_006509808.5

3734

XP_006509871.1

538

transcript variant X5

isoform X3

XM_036154395.1

2833

XP_036010288.1

498

transcript variant X2

isoform X2

XM_006509806.3

2842

XP_006509869.2

501

transcript variant X1

isoform X1

Known

NM_019313.1

1611

NP_062186.1

536

Predicted

XR_005494663.1

3842

transcript variant X14

XR_005494664.1

3833

transcript variant X15

XR_005494661.1

3949

transcript variant X12

XR_005494662.1

3940

transcript variant X13

XM_039094790.1

4381

XP_038950718.1

499

transcript variant X11

isoform X3

XM_017600232.2

4522

XP_017455721.1

536

transcript variant X4

isoform X1

XM_039094781.1

4489

XP_038950709.1

536

transcript variant X1

isoform X1

XM_039094789.1

4480

XP_038950717.1

533

transcript variant X10

isoform X2

XM_039094784.1

4104

XP_038950712.1

536

transcript variant X5

isoform X1

XM_039094783.1

4071

XP_038950711.1

536

transcript variant X3

isoform X1

XM_039094782.1

3079

XP_038950710.1

536

transcript variant X2

isoform X1

XM_039094788.1

2373

XP_038950716.1

536

transcript variant X9

isoform X1

XM_039094786.1

2339

XP_038950714.1

536

transcript variant X7

isoform X1

XM_039094787.1

2194

XP_038950715.1

536

transcript variant X8

isoform X1

XM_039094785.1

2311

XP_038950713.1

536

transcript variant X6

isoform X1

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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]

SK1 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	10712.92	source
Mouse	7392.84	source
Rat	5233.51	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 [544], [142]thereby potentially contributing to neuronal excitability control and they are critical regulators of neuronal excitability in hippocampus [1106]).

SK1 is expressed, from highest to lowest levels in: amígdala, hippocampus, caudate nucleus, cerebellum , thalamus, substantia nigra, spinal cord and pituitary gland. [539]. SK1 and SK2 are often expressed in the same neurons, predominantly in the neocortex, hippocampal formation, cerebellum, and thalamus [1479]).

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]).

Perpheral tissue [1482], [539]

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

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CNS Sub-cellular Distribution

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

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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).

148

Shah M et al. The pharmacology of hSK1 Ca2+-activated K+ channels expressed in mammalian cell lines.
Br. J. Pharmacol., 2000 Feb , 129 (627-30).

157

Barfod ET et al. Cloning and functional expression of a liver isoform of the small conductance Ca2+-activated K+ channel SK3.
Am. J. Physiol., Cell Physiol., 2001 Apr , 280 (C836-42).

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).

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).

1482

Chen MX et al. Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum.
Naunyn Schmiedebergs Arch. Pharmacol., 2004 Jun , 369 (602-15).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/65/ , accessed on 2024 Nov 21

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