Calcium-activated potassium channel impairing toxin ~ VenomZone

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/Insect	Snake	Scorpion	Cone snail	Spider	Cnidarian	Insect	Other	All
KCa1.1/KCNMA1 (large conductance)				-	-	-	-
KCa2.1/KCNN1/SK1 (small conductance)		-		-	-	-		-
KCa2.2/KCNN2/SK2 (small conductance)		-		-	-	-		-
KCa2.3/KCNN3/SK3 (small conductance)		-		-	-	-		-
KCa3.1/KCNN4/IK/SK4 (small conductance)		-		-	-	-	-	-
Insect KCa - Slo-type		-	-	-		-	-	-
KCa all				-		-

Calcium-activated potassium channel impairing toxin

Venom protein entries in UniProtKB/Swiss-Prot

CRISP family

Invertebrate defensin family, Type 2 subfamily

Natriuretic peptide family

Neurotoxin 11 (kappa toxin) family

Neurotoxin 30 (phrixotoxin) family

Not in a family

O2 superfamily, Contryphan family

Phospholipase A2 family, Group I subfamily

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Venom Kunitz-type family