Heteroscodratoxin-1 (also known as κ-theraphototoxin-Hm1a, κ-TRTX-Hm1a, δ-theraphotoxin-Hm1a, δ-TRTX-Hm1a, Hm1a or HmTx1) is a neurotoxin produced by the venom glands of Heteroscodra maculata (Togo starburst tarantula) that shifts the activation threshold of voltage-gated potassium channels and the inactivation of Nav1.1 sodium channels to more positive potentials. Sources Heteroscodratoxin-1 can be obtained from venom glands of Heteroscodra maculata (Togo starburst tarantula or Togo starburst baboon spider). Chemistry Heteroscodratoxin-1 is a basic protein (isoelectric point of 7.7) composed of 35 amino acids with a carboxylated C-terminus. Its sequence shows strong similarity with other tarantula toxins such as scodratoxin, hanatoxin and SGTx1. Structurally the protein belongs to the huwentoxin-1 family of inhibitory spider peptides based on its knottin backbone that consists of three crossing disulfide bridges (Cys1-Cys4/Cys2-Cys5/Cys3-Cys6). Hm1a has the following amino acid sequence: ECRYLFGGCSSTSDCCKHLSCRSDWKYCAWDGTFS. Its molecular weight is 3,995.61 Da. Target Heteroscodratoxin-1 inhibits subtypes of both delayed rectifier (KV2.1 and KV2.2) and A-type rapidly inactivating (KV4.1, KV4.2 and KV4.3) voltage-gated potassium channels. At a concentration of 100-300 nM, in transfected COS cells it blocks 23% of KV2.1, 19% of KV2.2, 50% of KV4.1, 39% of KV4.2, and 43% of KV4.3 conductance at a potential of 0 mV. No significant effect on other A-type rapidly inactivating (KV1.4 and KV3.4) or delayed rectifier potassium channels (KV1.1, KV1.2, KV1.3, KV1.5, KV1.6, KV1.2/ KV1.5, or KVLQT1), or on sodium and calcium channels has been observed. Physiologically probably more important than its action on potassium channels is its action on the voltage-gated sodium channel Nav1.1 (EC50 = 38 ± 6 nM). More specifically, it is thought that Hm1a targets the domain IV S3-S4 loop and the S1-S2 loop of Nav1.1, as application of this toxin to a chimeric channel which contained these regions resulted in full toxin sensitivity (compared to other chimeric channels which contained only one of either of these regions). This, therefore, indicates that both the S1-S2 and the S3-S4 domains determine toxin sensitivity and selectivity. Hm1a enhances the Nav1.1 channel activity by inhibiting fast and slow inactivation of the channel. Hm1a prevents the movement of the voltage sensor domain IV. Hm1a and Hm1b prevent the movement of the sensor domain towards the inner part of the cell thereby inhibiting fast inactivation of the Nav1.1 channel. Hm1a also inhibits the slow inactivation of the Nav1.1 channel by preventing a current reduction in the ion channel, but the underlying mechanism has not yet been elucidated. Mode of