SK3

Description: potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3
Gene: Kcnn3
Alias: SK3, hSK3, SKCA3, KCa2.3, KCNN3

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Introduction

Small conductance Ca2+ -activated K+ channels (SK chan- nels) are important regulators of excitability, endogenous firing pattern and synaptic integration in many neurons (Bond et al., 2005 [1104]).

Pyramidal neurons of the cortex and hippocampus display a calcium-activated slow afterhyperpolarization (sAHP) that plays a key role in regulating cell firing (Schwindt et al., 1988a [1094],b [1095]; Stocker et al., 1999 [550]) and is the target for regulation by multiple neurotransmitters (Nicoll, 1988 [1096]). Biophysical and electrophysiological studies have suggested that this sAHP is mediated by a calcium-activated potassium current. However, despite extensive studies, the identity of the ion channels underlying the sAHP remains uncertain (Sah and Faber, 2002 [1097]; Vogalis et al., 2003 [13). In the mid-1990s, with the discovery of the SKCa family of potassium channels (KCa2.x) (Kohler et al., 1996 [1099]; Gutman et al., 2003 [760]), the search for the ion channels responsible for the sAHP appeared to have reached fruition (Vergara et al., 1998 [1100]; Bond et al., 1999 [1101]). But the slow AHP current in a transgeneic mouse, expressing a truncated SKCa subunit (SK3-1B) capable of acting as a dominant negative for the entire family of SKCa–IKCa channels contradicted those findings: Expression of SK3-1B profoundly inhibited medium AHP current but again had no discernable effect on IsAHP. These results are inconsistent with the proposal that SKCa channels mediate IsAHP in pyramidal cells and indicate that a different potassium channel mediates this current. (Villalobos [142])

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Gene

Species	NCBI gene ID	Chromosome	Position
Human	3782	1	172826
Mouse	140493	3	152330
Rat	54263	2	159064

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Transcript

Species	NCBI accession	Length (nt)
Human	NM_002249.6	13034
Mouse	NM_080466.2	7617
Rat	NM_019315.3	2518

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Protein Isoforms

Species	Uniprot ID	Length (aa)
Human	Q9UGI6	731
Mouse	P58391	732
Rat	P70605	732

Isoforms

Transcript

Length (nt)

Protein

Length (aa)

Variant

Isoform

Known

NM_002249.6

13034

NP_002240.3

731

transcript variant 1

isoform a

NM_001204087.2

13079

NP_001191016.1

746

transcript variant 3

isoform c

NM_170782.3

11966

NP_740752.1

426

transcript variant 2

isoform b

NM_001365838.1

11899

NP_001352767.1

418

transcript variant 5

isoform e

NM_001365837.1

11944

NP_001352766.1

433

transcript variant 4

isoform d

Known

NM_019315.3

2518

NP_062188.3

731

Predicted

XM_017591053.2

9071

XP_017446542.1

418

transcript variant X5

isoform X3

XM_039102982.1

10226

XP_038958910.1

699

transcript variant X1

isoform X1

XM_039102983.1

9694

XP_038958911.1

424

transcript variant X2

isoform X2

XM_039102986.1

9594

XP_038958914.1

418

transcript variant X4

isoform X3

XM_039102988.1

9435

XP_038958916.1

418

transcript variant X7

isoform X3

XM_039102987.1

9272

XP_038958915.1

418

transcript variant X6

isoform X3

XM_039102985.1

9054

XP_038958913.1

418

transcript variant X3

isoform X3

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Post-Translational Modifications

PTM

Position

Type

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Structure

SK channels and the peripherally expressed intermediate conductance Ca2+ -activated K+ channel (IK; Ishii et al., 1997), constitute a molecular family of voltage-independent channels, that are gated by Ca2+ binding to calmodulin (CAM) tightly associated with a CAM- binding domain (CAMBD) in the C-terminal region (Xia et al., 1998 [542]; Khanna et al., 1999 [1105]). Crystallographic data from C-terminal peptides of the SK2 channel indicate that dimers of CAMBD associate with two CAM molecules, each binding 1 or 2 Ca2+ at the EF hand motifs 1 and 2 (Schumacher et al., 2001 [543]).

SK3 predicted AlphaFold size

Species	Area (Å²)	Reference
Human	6956.27	source
Mouse	7677.78	source
Rat	8715.98	source

Methodology for AlphaFold size prediction and disclaimer are available here

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Expression and Distribution

Central nervous system

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]

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

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

SK3 channels in muscle cells are crucial for pregnancy progresses such as myometrial tranquility. SK3 channels are the first channels for which overexpression led to a delay or cessation of parturition (Pierce [154], Bond [1101]).

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Interaction

Native SK channels have a characteristic pharmacology. They can be blocked by the bee venom toxin apamin and several selective small molecule blockers that we have developed (such as UCL 1848) that are active at nanomolar or subnanomolar concentrations (Chen [1102], Faber [1103]).

SK3 forms functional heteromeric channels with SK1 and SK2. (Monaghan [2])

CyPPA was found to be a positive modulator of hSK3. (Hougaard [155])

References

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).

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).

154

Pierce SL et al. Overexpression of SK3 channels dampens uterine contractility to prevent preterm labor in mice.
Biol. Reprod., 2008 Jun , 78 (1058-63).

155

Hougaard C et al. Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels.
Br. J. Pharmacol., 2007 Jul , 151 (655-65).

156

Hosseini R et al. SK3 is an important component of K(+) channels mediating the afterhyperpolarization in cultured rat SCG neurones.
J. Physiol. (Lond.), 2001 Sep 1 , 535 (323-34).

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).

158

Bond CT et al. Respiration and parturition affected by conditional overexpression of the Ca2+-activated K+ channel subunit, SK3.
Science, 2000 Sep 15 , 289 (1942-6).

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).

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).

760

Gutman GA et al. International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: potassium channels.
Pharmacol. Rev., 2003 Dec , 55 (583-6).

1094

Schwindt PC et al. Influence of anomalous rectifier activation on afterhyperpolarizations of neurons from cat sensorimotor cortex in vitro.
J. Neurophysiol., 1988 Feb , 59 (468-81).

1095

Schwindt PC et al. Slow conductances in neurons from cat sensorimotor cortex in vitro and their role in slow excitability changes.
J. Neurophysiol., 1988 Feb , 59 (450-67).

1096

Nicoll RA The coupling of neurotransmitter receptors to ion channels in the brain.
Science, 1988 Jul 29 , 241 (545-51).

1097

Sah P et al. Channels underlying neuronal calcium-activated potassium currents.
Prog. Neurobiol., 2002 Apr , 66 (345-53).

1098

Vogalis F et al. SK channels and the varieties of slow after-hyperpolarizations in neurons.
Eur. J. Neurosci., 2003 Dec , 18 (3155-66).

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).

1101

Bond CT et al. Small-conductance calcium-activated potassium channels.
Ann. N. Y. Acad. Sci., 1999 Apr 30 , 868 (370-8).

1102

Chen JQ et al. bis-Quinolinium cyclophanes: 8,14-diaza-1,7(1, 4)-diquinolinacyclotetradecaphane (UCL 1848), a highly potent and selective, nonpeptidic blocker of the apamin-sensitive Ca(2+)-activated K(+) channel.
J. Med. Chem., 2000 Sep 21 , 43 (3478-81).

1103

Faber ES et al. Physiological role of calcium-activated potassium currents in the rat lateral amygdala.
J. Neurosci., 2002 Mar 1 , 22 (1618-28).

1104

Bond CT et al. SK channels in excitability, pacemaking and synaptic integration.
Curr. Opin. Neurobiol., 2005 Jun , 15 (305-11).

1105

Khanna R et al. hSK4/hIK1, a calmodulin-binding KCa channel in human T lymphocytes. Roles in proliferation and volume regulation.
J. Biol. Chem., 1999 May 21 , 274 (14838-49).

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).

1481

Pedarzani P et al. Molecular and cellular basis of small--and intermediate-conductance, calcium-activated potassium channel function in the brain.
Cell. Mol. Life Sci., 2008 Oct , 65 (3196-217).

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).

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).

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To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/67/ , accessed on 2024 Apr 27

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