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 species (browse by taxonomy, browse by keywords)

1 entry

Androctonus australis (Sahara scorpion)

KAX35_ANDAU Potassium channel toxin alpha-KTx 3.5 (Kaliotoxin-2) (KTX-2) Short scorpion toxin ...

2 entries

Androctonus mauritanicus mauritanicus (Scorpion)

Select_allDeselect_all
KAX52_ANDMA Potassium channel toxin alpha-KTx 5.2 (AmP05) (Leiurotoxin ... Short scorpion toxin ...
KAX81_ANDMA Potassium channel toxin alpha-KTx 8.1 (AmP01) (Neurotoxin P01) Short scorpion toxin ...

1 entry

Apis cerana cerana (Oriental honeybee)

APAM_APICC Apamin Not in a family

2 entries

Apis mellifera (Honeybee)

Select_allDeselect_all
APAM_APIME Apamin Not in a family
TERT_APIME Tertiapin (TPN) Not in a family

1 entry

Buthus occitanus tunetanus (Common European scorpion)

KAX95_BUTOC Potassium channel toxin alpha-KTx 9.5 (Neurotoxin Kbot1) Short scorpion toxin ...

2 entries

Buthus paris (Scorpion) (Buthus occitanus paris)

Select_allDeselect_all
KA168_BUTPA Potassium channel toxin alpha-KTx 16.8 (Toxin BoP1) Short scorpion toxin ...
KA169_BUTPA Potassium channel toxin alpha-KTx 16.9 (Toxin BoP2) Short scorpion toxin ...

1 entry

Centruroides limbatus (Bark scorpion)

KAX14_CENLM Potassium channel toxin alpha-KTx 1.4 (Limbatotoxin) (LbTx) ... Short scorpion toxin ...

1 entry

Centruroides limpidus (Mexican scorpion) (Centruroides limpidus limpidus)

KAX27_CENLI Potassium channel toxin alpha-KTx 2.7 (C.1.limpidus toxin 2) ... Short scorpion toxin ...

3 entries

Centruroides noxius (Mexican scorpion)

Select_allDeselect_all
KA101_CENNO Potassium channel toxin alpha-KTx 10.1 (Cobatoxin-1) (CoTx1) ... Short scorpion toxin ...
KAX1B_CENNO Potassium channel toxin alpha-KTx 1.11 (Slotoxin) (SloTx) Short scorpion toxin ...
KAX21_CENNO Potassium channel toxin alpha-KTx 2.1 (Noxiustoxin) (NTx) (Toxin ... Short scorpion toxin ...

1 entry

Centruroides tecomanus (Scorpion) (Centruroides limpidus tecomanus)

KAX2F_CENTE Potassium channel toxin alpha-KTx 2.15 (Toxin II.10.5) Short scorpion toxin ...

1 entry

Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps)

VNP_DENAN Natriuretic peptide DNP Natriuretic peptide family

1 entry

Hadronyche formidabilis (Northern tree funnel-web spider) (Atrax formidabilis)

TK1A_HADFO Kappa-hexatoxin-Hf1a (Kappa-HXTX-Hf1a) (Janus-atracotoxin-Hf1a) ... Shiva superfamily, Kappa toxin ...

1 entry

Hadronyche modesta (Victorian funnel-web spider)

TK1A_HADMO Kappa-hexatoxin-Hmo1d Shiva superfamily, Kappa toxin ...

5 entries

Hadronyche versuta (Blue mountains funnel-web spider) (Atrax versutus)

Select_allDeselect_all
TK1A_HADVE Kappa-hexatoxin-Hv1a (Kappa-HXTX-Hv1a) (Janus-atracotoxin-Hv1a) ... Shiva superfamily, Kappa toxin ...
TK1B_HADVE Kappa-hexatoxin-Hv1b (Kappa-HXTX-Hv1b) (Janus-atracotoxin-Hv1b) ... Shiva superfamily, Kappa toxin ...
TK1C_HADVE Kappa-hexatoxin-Hv1c (Kappa-HXTX-Hv1c) (Janus-atracotoxin-Hv1c) ... Shiva superfamily, Kappa toxin ...
TK1D_HADVE Kappa-hexatoxin-Hv1d Shiva superfamily, Kappa toxin ...
TK1E_HADVE Kappa-hexatoxin-Hv1e Shiva superfamily, Kappa toxin ...

1 entry

Hemachatus haemachatus (Rinkhals) (Sepedon haemachatus)

CRVP_HEMHA Cysteine-rich venom protein hematin (CRVP) (Fragment) CRISP family

1 entry

Heterometrus spinifer (Asia giant forest scorpion) (Malaysian black scorpion)

KAX63_HETSP Potassium channel toxin alpha-KTx 6.3 (Neurotoxin HsTX1) Short scorpion toxin ...

6 entries

Leiurus quinquestriatus hebraeus (Yellow scorpion)

Select_allDeselect_all
KA165_LEIQH Potassium channel toxin alpha-KTx 16.5 (Lqh 15-1) (Toxin 15-1) ... Short scorpion toxin ...
KAX11_LEIQH Potassium channel toxin alpha-KTx 1.1 (ChTX-Lq1) (ChTx-a) ... Short scorpion toxin ...
KAX12_LEIQH Potassium channel toxin alpha-KTx 1.2 (ChTX-Lq2) (ChTx-d) ... Short scorpion toxin ...
KAX1C_LEIQH Potassium channel toxin alpha-KTx 1.12 (Charybdotoxin b) ... Short scorpion toxin ...
KAX1D_LEIQH Potassium channel toxin alpha-KTx 1.13 (Charybdotoxin c) ... Short scorpion toxin ...
KAX51_LEIQH Potassium channel toxin alpha-KTx 5.1 (Leiurotoxin I) (LeTx I) ... Short scorpion toxin ...

1 entry

Mesobuthus gibbosus (Mediterranean checkered scorpion)

KA145_MESGB Potassium channel toxin alpha-KTx 14.5 (Toxin Mgib29) Short scorpion toxin ...

14 entries

Mesobuthus martensii (Manchurian scorpion) (Buthus martensii)

Select_allDeselect_all
KA142_MESMA Potassium channel toxin alpha-KTx 14.2 (BmKK2) (BmTXKS3) (KK1) ... Short scorpion toxin ...
KA144_MESMA Potassium channel toxin alpha-KTx 14.4 (BmSKTx1) (Neurotoxin ... Short scorpion toxin ...
KA162_MESMA Potassium channel toxin alpha-KTx 16.2 (BmK 622) (BmTx3B) ... Short scorpion toxin ...
KA163_MESMA Potassium channel toxin alpha-KTx 16.3 (Charybdotoxin-like toxin ... Short scorpion toxin ...
KA191_MESMA Potassium channel toxin alpha-KTx 19.1 (BmK37) (Neurotoxin ... Short scorpion toxin ...
KAX15_MESMA Potassium channel toxin alpha-KTx 1.5 (BmTX1) (Neurotoxin TX1) Short scorpion toxin ...
KAX16_MESMA Potassium channel toxin alpha-KTx 1.6 (BmTX2) (Neurotoxin TX2) Short scorpion toxin ...
KAX1E_MESMA Potassium channel toxin alpha-KTx 1.14 (BmKcug1) (Kcug1) Short scorpion toxin ...
KAX1F_MESMA Potassium channel toxin alpha-KTx 1.15 (BmKcug2) (Kcug1) Short scorpion toxin ...
KAX1X_MESMA Potassium channel toxin alpha-KTx BmKcug1a (Kcug1a) Short scorpion toxin ...
KAX53_MESMA Potassium channel toxin alpha-KTx 5.3 (Neurotoxin BmP05) ... Short scorpion toxin ...
KAX82_MESMA Potassium channel toxin alpha-KTx 8.2 (Neurotoxin BmP01) ... Short scorpion toxin ...
KAX91_MESMA Potassium channel toxin alpha-KTx 9.1 (BmKK6) (Neurotoxin BmP02) ... Short scorpion toxin ...
KAX92_MESMA Potassium channel toxin alpha-KTx 9.2 (Neurotoxin BmP03) ... Short scorpion toxin ...

4 entries

Mesobuthus tamulus (Eastern Indian scorpion) (Buthus tamulus)

Select_allDeselect_all
KA161_MESTA Potassium channel toxin alpha-KTx 16.1 (Alpha-KTx 1.8) ... Short scorpion toxin ...
KAX13_MESTA Potassium channel toxin alpha-KTx 1.3 (Iberiotoxin) (IbTx) Short scorpion toxin ...
KAX54_MESTA Potassium channel toxin alpha-KTx 5.4 (Tamapin) Short scorpion toxin ...
KAX55_MESTA Potassium channel toxin alpha-KTx 5.5 (Tamapin-2) Short scorpion toxin ...

2 entries

Naja annulifera (Banded Egyptian cobra) (Naja haje annulifera)

Select_allDeselect_all
CRVPA_NAJHA Cysteine-rich venom protein annuliferin-a (CRVP) (Fragment) CRISP family
CRVPB_NAJHA Cysteine-rich venom protein annuliferin-b (CRVP) (Fragment) CRISP family

1 entry

Naja atra (Chinese cobra)

"Naja atra" VenomZone page
CRVP1_NAJAT Cysteine-rich venom protein natrin-1 (Cysteine-rich venom ... CRISP family

1 entry

Naja kaouthia (Monocled cobra) (Naja siamensis)

CRVP1_NAJKA Cysteine-rich venom protein kaouthin-1 (Cysteine-rich venom ... CRISP family

1 entry

Naja mossambica (Mozambique spitting cobra)

"Naja mossambica" VenomZone page
CRVP_NAJMO Cysteine-rich venom protein mossambin (CRVP) (Fragment) CRISP family

1 entry

Orthochirus scrobiculosus (Central Asian scorpion)

KAX37_ORTSC Potassium channel toxin alpha-KTx 3.7 (OsK-1) (OsK1) Short scorpion toxin ...

1 entry

Ovophis okinavensis (Ryukyu Island pit viper) (Trimeresurus okinavensis)

CRVP_OVOOK Cysteine-rich venom protein okinavin (CRVP) (Fragment) CRISP family

3 entries

Oxyuranus scutellatus scutellatus (Australian taipan) (Coastal taipan)

Select_allDeselect_all
3L2L_OXYSC Taicatoxin, alpha-neurotoxin-like component (TCX, ... Snake three-finger toxin family, ...
PA2T_OXYSC Phospholipase A2 taicatoxin (TCX) (svPLA2) (EC 3.1.1.4) ... Phospholipase A2 family, Group I ...
VKT_OXYSC Kunitz-type serine protease inhibitor taicotoxin (Taicatoxin, ... Venom Kunitz-type family

2 entries

Pandinus imperator (Emperor scorpion)

Select_allDeselect_all
KAX61_PANIM Potassium channel toxin alpha-KTx 6.1 (PiTX-K-gamma) (Potassium ... Short scorpion toxin ...
KAX64_PANIM Potassium channel toxin alpha-KTx 6.4 (Potassium ... Short scorpion toxin ...

1 entry

Rhopalurus junceus (Caribbean blue scorpion)

KA118_RHOJU Potassium channel toxin alpha-KTx 1.18 (Peptide Rj1m1) Short scorpion toxin ...

1 entry

Scorpio palmatus (Israeli golden scorpion) (Scorpio maurus palmatus)

KAX62_SCOPA Potassium channel toxin alpha-KTx 6.2 (Maurotoxin) (MTX) Short scorpion toxin ...

1 entry

Tityus costatus (Brazilian scorpion)

KA123_TITCO Potassium channel toxin alpha-KTx 12.3 (Butantoxin-like peptide) ... Short scorpion toxin ...

2 entries

Tityus serrulatus (Brazilian scorpion)

Select_allDeselect_all "Tityus serrulatus" VenomZone page
KA121_TITSE Potassium channel toxin alpha-KTx 12.1 (Butantoxin) (BuTX) (Ts6) ... Short scorpion toxin ...
KAX42_TITSE Potassium channel toxin alpha-KTx 4.2 (Neurotoxin Ts-kappa) ... Short scorpion toxin ...

1 entry

Tityus stigmurus (Brazilian scorpion)

KA124_TITST Potassium channel toxin alpha-KTx 12.4 (Butantoxin) (BuTX) ... Short scorpion toxin ...

1 entry

Tityus trivittatus (Argentinean scorpion)

KA122_TITTR Potassium channel toxin alpha-KTx 12.2 (Butantoxin) (BuTX) ... Short scorpion toxin ...