Calcium-activated potassium channel impairing toxin

Channel Calcium-activated potassium (KCa) channels are widely expressed in neuronal and nonneuronal tissues including epithelia, smooth muscle, and sensory cells where they couple membrane potential and   intracellular    Ca2+   concentration [Ca2]i.   Activated
upon an increase in [Ca2 ]i, KCa channels give rise to an efflux of potassium which via re/hyperpolarization of the membrane potential feeds back onto [Ca2 ]i by limiting calcium influx either through deactivation of voltage-gated calcium (Cav) channels or through increased transport activity of Na+ /Ca2+ exchangers. Accordingly, KCa channels shape the amplitude and duration of calcium transients and thus affect the downstream signaling pathways that are triggered by changes in [Ca2]i (Berkefeld et al., 2010 and references therein).

KCa are classified into two types, the large conductance (BKCa channels), and the smaller conductance (SKCa channels). Both are homotetramers and both contain an integral membrane domain. The BKCa and SKCa channels, however, show very little sequence homology, and they have evolved unique intracellular sequences to permit calcium sensing (Cox, 2011 ).

Figure 1: Membrane topology of BKCa channel, α subunit (Cox, 2011 published in BMB Reports and licensed under Creative Commons. )

Large conductance calcium-activated potassium channels
The pore-forming α subunits of BKCa channels are encoded by the gene KCa1.1/KCNM1. BKCa channels are composed of four identical pore-forming α subunits, and in some tissues auxiliary β subunits. The α subunits alone are sufficient to form a functional channel, while the β subunits play a modulatory role. BKCa has an integral-membrane domain and it has an extra transmembrane domain (S0) that places its N-terminus outside the cell. It also has a very large intracellular C-terminus (about 800 amino acids) that is unique to this channel and appears to have evolved to confer calcium sensitivity. Indeed, BKCa channels are both calcium and voltage activated, and there is a synergy between these stimuli that is seen as a leftward shifting of the channel’s conductance-voltage relation (G-V), as the internal calcium concentration is raised. Surprisingly, BKCa’s amino-acid sequence contains no canonical calcium binding motifs (EF hand or C2 domains). The BKCa subunit appears to contain three types of Ca2+ binding sites, one of low affinity that lies in a region of the channel’s large C-terminus proximal to the membrane known as the RCK1 domain, and two of higher affinity, one that also lies within the RCK1 domain and another that lies further downstream in a region of the channel known as the Ca2+ bowl (Cox, 2011 and references therein).

Small conductance calcium-activated potassium channels
The pore-forming α subunits of SKCa channels are encoded by four homologous genes (KCa2.1/KCNN1, KCa2.2/KCNN2, KCa2.3/KCNN3 and KCa3.1/KCNN4 (this latter is also termed intermediate-conductance K+ channel)). Although sharing the tetrameric six-transmembrane domain architecture of voltage-gated cation channels, they lack the typical features of voltage-sensing S4 segments (Fig.2). Consequently, the gating of SKCa channels is fully independent of the transmembrane voltage, in contrast to BKCa channels. Instead, opening and closing of SKCa channels is solely driven by changes in [Ca2 ]i, with submicromolar concentrations being sufficient to effectively gate the channels (Berkefeld et al., 2010 and references therein).
SKCa channels contain no canonical Ca2+ binding motifs. Unlike to BKCa channel, their Ca2+ sensitivity is explained by the constitutive association of the ubiquitous Ca2+-binding protein calmodulin (CaM) (UniProtKB and wikipedia ) which binds each SKCa subunit, giving four CaM per channel. CaM has been found to associate with target proteins in a Ca2+-independent manner, as is the case with the SKCa channel. Most such interactions occur through the well characterized IQ domain (UniProtKB and wikipedia ). Surprisingly, however, none of the SK subunits contain such a motif. Thus, the nature of their constitutive association with CaM is considered novel and perhaps unique (Cox, 2011 and references therein).
Figure 2: Membrane topology of SKCa channel, α subunit (upload.wikimedia / Licensed under Creative Commons. )
Toxin
Channel Toxins from different taxa that target channels.
Click on to retrieve channels or toxins of interest.
Human Snake Scorpion Cone
snail
Spider Cnidarian Insect Other All
KCa1.1/KCNMA1
(large conductance)
- - - - -
KCa2.1/KCNN1
(small conductance)
- - - - - - - -
KCa2.2/KCNN2
(small conductance)
- - - - - - - -
KCa2.3/KCNN3
(small conductance)
- - - - - - - -
KCa3.1/KCNN4
(small conductance)
- - - - - -
KCa all - - - - -

Venom protein entries in UniProtKB/Swiss-Prot

69 entries grouped by family (browse by taxonomy, browse by keywords)

7 entries

CRISP family

Select_allDeselect_all "CRISP family" VenomZone page
CRVP1_NAJAT Cysteine-rich venom protein natrin-1 ... Naja atra (Chinese cobra)
CRVP1_NAJKA Cysteine-rich venom protein kaouthin-1 ... Naja kaouthia (Monocled cobra) (Naja siamensis)
CRVPA_NAJHA Cysteine-rich venom protein annuliferin-a (CRVP) ... Naja annulifera (Banded Egyptian cobra) (Naja ...
CRVPB_NAJHA Cysteine-rich venom protein annuliferin-b (CRVP) ... Naja annulifera (Banded Egyptian cobra) (Naja ...
CRVP_HEMHA Cysteine-rich venom protein hematin (CRVP) ... Hemachatus haemachatus (Rinkhals) (Sepedon ...
CRVP_NAJMO Cysteine-rich venom protein mossambin (CRVP) ... Naja mossambica (Mozambique spitting cobra)
CRVP_OVOOK Cysteine-rich venom protein okinavin (CRVP) ... Ovophis okinavensis (Ryukyu Island pit viper) ...

1 entry

Natriuretic peptide family

"Natriuretic peptide family" VenomZone page
VNP_DENAN Natriuretic peptide DNP Dendroaspis angusticeps (Eastern green mamba) ...

7 entries

Neurotoxin 11 (kappa toxin) family

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TK1A_HADFO Kappa-hexatoxin-Hf1a (Kappa-HXTX-Hf1a) ... Hadronyche formidabilis (Northern tree ...
TK1A_HADMO Kappa-hexatoxin-Hmo1d Hadronyche modesta (Victorian funnel-web spider)
TK1A_HADVE Kappa-hexatoxin-Hv1a (Kappa-HXTX-Hv1a) ... Hadronyche versuta (Blue mountains funnel-web ...
TK1B_HADVE Kappa-hexatoxin-Hv1b (Kappa-HXTX-Hv1b) ... Hadronyche versuta (Blue mountains funnel-web ...
TK1C_HADVE Kappa-hexatoxin-Hv1c (Kappa-HXTX-Hv1c) ... Hadronyche versuta (Blue mountains funnel-web ...
TK1D_HADVE Kappa-hexatoxin-Hv1d Hadronyche versuta (Blue mountains funnel-web ...
TK1E_HADVE Kappa-hexatoxin-Hv1e Hadronyche versuta (Blue mountains funnel-web ...

3 entries

Not in a family

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APAM_APICC Apamin Apis cerana cerana (Oriental honeybee)
APAM_APIME Apamin (Apamine) Apis mellifera (Honeybee)
TERT_APIME Tertiapin (TPN) Apis mellifera (Honeybee)

1 entry

O2 superfamily, Contryphan family

COW_CONVE Contryphan-Vn Conus ventricosus (Mediterranean cone)

1 entry

Phospholipase A2 family, Group I subfamily

"Phospholipase A2 family" VenomZone page
PA2T_OXYSC Phospholipase A2 taicatoxin (TCX) (svPLA2) (EC ... Oxyuranus scutellatus scutellatus (Australian ...

13 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 01 subfamily

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KAX11_LEIHE Potassium channel toxin alpha-KTx 1.1 (ChTX-Lq1) ... Leiurus hebraeus (Deathstalker scorpion) ...
KAX12_LEIHE Potassium channel toxin alpha-KTx 1.2 (ChTX-Lq2) ... Leiurus hebraeus (Deathstalker scorpion) ...
KAX13_HOTTA Potassium channel toxin alpha-KTx 1.3 ... Hottentotta tamulus (Eastern Indian scorpion) ...
KAX14_CENLM Potassium channel toxin alpha-KTx 1.4 ... Centruroides limbatus (Bark scorpion)
KAX15_MESMA Potassium channel toxin alpha-KTx 1.5 (BmTX1) ... Mesobuthus martensii (Manchurian scorpion) ...
KAX16_MESMA Potassium channel toxin alpha-KTx 1.6 (BmTX2) ... Mesobuthus martensii (Manchurian scorpion) ...
KAX1B_CENNO Potassium channel toxin alpha-KTx 1.11 ... Centruroides noxius (Mexican scorpion)
KAX1C_LEIHE Potassium channel toxin alpha-KTx 1.12 ... Leiurus hebraeus (Deathstalker scorpion) ...
KAX1D_LEIHE Potassium channel toxin alpha-KTx 1.13 ... Leiurus hebraeus (Deathstalker scorpion) ...
KAX1E_MESMA Potassium channel toxin alpha-KTx 1.14 (BmKcug1) ... Mesobuthus martensii (Manchurian scorpion) ...
KAX1F_MESMA Potassium channel toxin alpha-KTx 1.15 (BmKcug2) ... Mesobuthus martensii (Manchurian scorpion) ...
KAX1I_RHOJU Potassium channel toxin alpha-KTx 1.18 (Peptide ... Rhopalurus junceus (Caribbean blue scorpion)
KAX1X_MESMA Potassium channel toxin alpha-KTx BmKcug1a ... Mesobuthus martensii (Manchurian scorpion) ...

3 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 02 subfamily

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KAX21_CENNO Potassium channel toxin alpha-KTx 2.1 ... Centruroides noxius (Mexican scorpion)
KAX27_CENLI Potassium channel toxin alpha-KTx 2.7 ... Centruroides limpidus (Mexican scorpion)
KAX2F_CENTE Potassium channel toxin alpha-KTx 2.15 (Toxin ... Centruroides tecomanus (Scorpion) (Centruroides ...

2 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 03 subfamily

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KAX35_ANDAU Potassium channel toxin alpha-KTx 3.5 ... Androctonus australis (Sahara scorpion)
KAX37_ORTSC Potassium channel toxin alpha-KTx 3.7 (OsK-1) ... Orthochirus scrobiculosus (Central Asian ...

1 entry

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 04 subfamily

KAX42_TITSE Potassium channel toxin alpha-KTx 4.2 ... Tityus serrulatus (Brazilian scorpion)

5 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 05 subfamily

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KAX51_LEIHE Potassium channel toxin alpha-KTx 5.1 ... Leiurus hebraeus (Deathstalker scorpion) ...
KAX52_ANDMA Potassium channel toxin alpha-KTx 5.2 (AmPO5) ... Androctonus mauritanicus mauritanicus (Scorpion)
KAX53_MESMA Potassium channel toxin alpha-KTx 5.3 ... Mesobuthus martensii (Manchurian scorpion) ...
KAX54_HOTTA Potassium channel toxin alpha-KTx 5.4 (Tamapin) Hottentotta tamulus (Eastern Indian scorpion) ...
KAX55_HOTTA Potassium channel toxin alpha-KTx 5.5 ... Hottentotta tamulus (Eastern Indian scorpion) ...

3 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 06 subfamily

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KAX61_PANIM Potassium channel toxin alpha-KTx 6.1 ... Pandinus imperator (Emperor scorpion)
KAX63_HETSP Potassium channel toxin alpha-KTx 6.3 ... Heterometrus spinifer (Asia giant forest ...
KAX64_PANIM Potassium channel toxin alpha-KTx 6.4 (Potassium ... Pandinus imperator (Emperor scorpion)

1 entry

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 08 subfamily

KAX81_ANDMA Potassium channel toxin alpha-KTx 8.1 (AmP01) ... Androctonus mauritanicus mauritanicus (Scorpion)

3 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 09 subfamily

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KAX91_MESMA Potassium channel toxin alpha-KTx 9.1 (BmKK6) ... Mesobuthus martensii (Manchurian scorpion) ...
KAX92_MESMA Potassium channel toxin alpha-KTx 9.2 ... Mesobuthus martensii (Manchurian scorpion) ...
KAX95_BUTOC Potassium channel toxin alpha-KTx 9.5 (Kbot1) Buthus occitanus tunetanus (Common European ...

1 entry

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 10 subfamily

KA101_CENNO Potassium channel toxin alpha-KTx 10.1 ... Centruroides noxius (Mexican scorpion)

4 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 12 subfamily

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KA121_TITSE Potassium channel toxin alpha-KTx 12.1 ... Tityus serrulatus (Brazilian scorpion)
KA122_TITTR Potassium channel toxin alpha-KTx 12.2 ... Tityus trivittatus (Argentinean scorpion)
KA123_TITCO Potassium channel toxin alpha-KTx 12.3 ... Tityus costatus (Brazilian scorpion)
KA124_TITST Potassium channel toxin alpha-KTx 12.4 ... Tityus stigmurus (Brazilian scorpion)

3 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 14 subfamily

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KA142_MESMA Potassium channel toxin alpha-KTx 14.2 (BmKK2) ... Mesobuthus martensii (Manchurian scorpion) ...
KA144_MESMA Potassium channel toxin alpha-KTx 14.4 (BmSKTx1) ... Mesobuthus martensii (Manchurian scorpion) ...
KA145_MESGB Potassium channel toxin alpha-KTx 14.5 (Toxin ... Mesobuthus gibbosus (Mediterranean checkered ...

6 entries

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 16 subfamily

Select_allDeselect_all
KA161_HOTTA Potassium channel toxin alpha-KTx 16.1 ... Hottentotta tamulus (Eastern Indian scorpion) ...
KA162_MESMA Potassium channel toxin alpha-KTx 16.2 (BmK 622) ... Mesobuthus martensii (Manchurian scorpion) ...
KA163_MESMA Potassium channel toxin alpha-KTx 16.3 ... Mesobuthus martensii (Manchurian scorpion) ...
KA165_LEIHE Potassium channel toxin alpha-KTx 16.5 (Lqh ... Leiurus hebraeus (Deathstalker scorpion) ...
KA168_BUTPA Potassium channel toxin alpha-KTx 16.8 (Toxin ... Buthus paris (Scorpion) (Buthus occitanus paris)
KA169_BUTPA Potassium channel toxin alpha-KTx 16.9 (Toxin ... Buthus paris (Scorpion) (Buthus occitanus paris)

1 entry

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 19 subfamily

KA191_MESMA Potassium channel toxin alpha-KTx 19.1 (BmK37) ... Mesobuthus martensii (Manchurian scorpion) ...

1 entry

Short scorpion toxin superfamily, Potassium channel inhibitor family, Alpha-KTx 6 subfamily

KAX62_SCOPA Potassium channel toxin alpha-KTx 6.2 ... Scorpio palmatus (Israeli golden scorpion) ...

1 entry

Snake three-finger toxin family, Long-chain subfamily, Type II alpha-neurotoxin sub-subfamily

"Snake three-finger toxin family" VenomZone page
3L2L_OXYSC Taicatoxin, alpha-neurotoxin-like component ... Oxyuranus scutellatus scutellatus (Australian ...

1 entry

Venom Kunitz-type family

"Venom Kunitz-type family" VenomZone page
VKT_OXYSC Kunitz-type serine protease inhibitor taicotoxin ... Oxyuranus scutellatus scutellatus (Australian ...