Jingzhaotoxin-X, a gating modifier of Kv4.2 and Kv4. 3 potassium channels purified from the venom of the Chinese tarantula Chilobrachys jingzhao

The tarantula Chilobrachys jingzhao is one of the largest venomous spiders in China. In previous studies, we purified and characterized at least eight peptides from C. jingzhao venom. In this report, we describe the purification and characterization of Jingzhaotoxin-X (JZTX-X), which selectively blocks Kv4.2 and Kv4.3 potassium channels. Methods: JZTX-X was purified using a combination of cation-exchange HPLC and reverse-phase HPLC. The amino-acid sequence was determined by automated Edman degradation and confirmed by mass spectrometry (MS). Voltage-gated ion channel currents were recorded in HEK293t cells transiently transfected with a variety of ion channel constructs. In addition, the hyperalgesic activity of JZTX-X and the toxin´s effect on motor function were assessed in mice. Results: JZTX-X contained 31 amino acids, with six cysteine residues that formed three disulfide bonds within an inhibitory cysteine knot (ICK) topology. In whole-cell voltage-clamp experiments, JZTX-X inhibited Kv4.2 and Kv4.3 potassium channels in a concentration- and voltage-dependent manner, without affecting other ion channels (Kv1.1, 1.2, 1.3, 2.1, delayed rectifier potassium channels, high- and low-voltage-activated Ca2+ channels, and voltage-gated sodium channels Nav1.5 and 1.7). JZTX-X also shifted the voltage-dependent channel activation to more depolarized potentials, whereas extreme depolarization caused reversible toxin binding to Kv4.2 channels. JZTX-X shifted the Kv4.2 and Kv4.3 activities towards a resting state, since at the resting potential the toxin completely inhibited the channels, even in the absence of an applied physical stimulus. Intrathecal or intraplantar injection of JZTX-X caused a long-lasting decrease in the mechanical nociceptive threshold (hyperalgesia) but had no effect on motor function as assessed in the rotarod test. Conclusions: JZTX-X selectively suppresses Kv4.2 and Kv4.3 potassium channel activity in a concentration- and voltage-dependent manner and causes long-lasting mechanical hyperalgesia.(AU)

Spider venom peptides as potential drug candidates due to their anticancer and antinociceptive activities

Spider venoms are known to contain proteins and polypeptides that perform various functions including antimicrobial, neurotoxic, analgesic, cytotoxic, necrotic, and hemagglutinic activities. Currently, several classes of natural molecules from spider venoms are potential sources of chemotherapeutics against tumor cells. Some of the spider peptide toxins produce lethal effects on tumor cells by regulating the cell cycle, activating caspase pathway or inactivating mitochondria. Some of them also target the various types of ion channels (including voltage-gated calcium channels, voltage-gated sodium channels, and acid-sensing ion channels) among other pain-related targets. Herein we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against the pathophysiological conditions including cancer and pain.(AU)

Simulation and Validation of Cisco Habitat in Minnesota Lakes Using the Lethal-Niche Boundary Curve.

Fish survival in lakes is strongly influenced by water temperature and dissolved oxygen (DO) concentration. A one-dimensional (vertical) lake water quality model MINLAKE 2012 was calibrated in 23 Minnesota lakes and used to simulate daily water temperature and DO concentrations in 36 representative lake types under past (1992–2008) climate conditions and a future climate scenario (MIROC 3.2). The 36 representative Minnesota lake types were developed based on three maximum depths (Hmax = 4, 13, and 24 m), three surface areas (As = 0.2, 1.7, 10 km2), and four Secchi depths (SD = 1.2, 2.5, 4.5, and 7 m, from eutrophic to oligotrophic lake). A fish habitat model using the lethal-niche- boundary curve of adult cisco (Coregnous artedi, a cold-water fish species) was then developed to evaluate cisco oxythermal habitat and survival in Minnesota lakes.The fish habitat model was validated in the 23 Minnesota lakes of which 18 had cisco mortality while 5 had no cisco mortality in the unusually warm summer of 2006. Cisco lethal and habitable conditions in the 23 lakes simulated by the model had anoverall good agreement with observations in 2006. After model validation, cisco lethal days in the 36 lake types were modeled using simulated daily temperature and DO profiles from MINLAKE2012. Polymictic shallow lakes with lake geometry ratio As 0.25/Hmax> 5.2 m-0.5 were simulated to typically not support cisco oxythermal habitat under past climate conditions and the future climate scenario. Medium-depth lakes are projected to be most vulnerable to climate warming with most increase in the number of years with cisco kill (average increase 13 years out of 17 simulation years). Strongly stratified mesotrophic and oligotrophic deep lakes are possible to support cisco habitat under both past and future climate conditions, and these deep lakes are good candidates for cisco refuge lakes that should be protected against water quality deteriorations.