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Phrixotoxin-2 (PaTx2) has been isolated originally from the venom of the Chile fire tarantula Phrixotrichus auratus. Phrixotoxin-2 is a 31 amino acid peptide that contains three disulfide bridges. Phrixotoxin-2 specifically blocks recombinant Kv4.2 and Kv4.3 currents with IC50 values of 34 nM and 71 nM, respectively. It does so by altering the gating properties of the channels. The inhibition of Kv4.2 and Kv4.3 currents is fully reversible upon washout. Kv4.1 is only slightly sensitive to Phrixotoxin-2 (maximal block of 20 by 300 nM). Kv1, Kv2 and Kv3 channel subfamilies are insensitive to this toxin.
AA sequence : Tyr-Cys2-Gln-Lys-Trp-Met-Trp-Thr-Cys9-Asp-Glu-Glu-Arg-Lys-Cys15-Cys16-Glu-Gly-Leu-Val-Cys21-Arg-Leu-Trp-Cys25-Lys-Arg-Ile-Ile-Asn-Met-NH2
Disulfide bonds : Cys2-Cys16, Cys9-Cys21 and Cys15-Cys25
Length (aa) : 31
Formula : C169H259N49O43S8
Molecular Weight : 3921.71 Da
Appearance : white lyophilized solid
Solubility : water or saline buffer
CAS number : 221889-63-0
Source : Synthetic
Purity rate : > 95%
In the present study, two new peptides, phrixotoxins PaTx1 & PaTx2 (29-31 amino acids), which potently block A-type potassium currents, have been purified from the venom of the tarantula Phrixotrichus auratus. 2. Phrixotoxins specifically block Kv4.3 & Kv4.2 currents that underlie I(to1), with an 5 < IC50 < 70 nM, by altering the gating properties of these channels. 3. Neither are the Shaker (Kv1), Shab (Kv2) & Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear specific of the Shal (Kv4) subfamily of currents & also block I(to1) in isolated murine cardiomyocytes. 4. In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia & different degrees of atrioventricular block. 5. The analysis of the mouse electrocardiogram showed a dose-dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249 +/- 11 to 265 +/- 8 ms (P < 0.05). 6. It was concluded that phrixotoxins, are new & specific blockers of Kv4.3 & Kv4.2 potassium currents, & hence of I(to1) that will enable further studies of Kv4.2 & Kv4.3 channel &/or I(to1) expression.
Diochot S. E, et al. (1999) Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis. British Journal of Pharmacology. PMID: 10051143
Volume regulation is a necessary task for spermatozoa as the osmolarity of female tract fluids is lower than that in the epididymis & because the disruption of it in transgenic mice results in infertility. As the specific mechanisms behind this phenomenon are unknown, spermatozoa from mice were screened for sensitivities to inhibitors known to affect specific channels involved in volume regulation of somatic cells. Spermatozoa from the cauda epididymidis were exposed to physiological hypotonic conditions with & without inhibitor. Flow cytometric forward scatter measurements were taken to indicate relative sperm size at 5 & 75 min of incubation. The presence of quinine (0.8 mM), cadmium (0.2 mM), flecainide (100 microM), 4-aminopyridine (4 mM), barium (1 mM), clofilium (10 microM), & phrixotoxin (100 nM) for 75 min resulted in significantly higher forward scatter values than sperm incubated in medium without an inhibitor. These results imply that channels potentially involved in volume regulation of murine spermatozoa include the voltage-dependent Kv1.4 (also known as KCNA1), Kv1.5 (KCNA5), Kv4.1 (KCND1), Kv4.2 (KCND2), Kv4.3 (KCND3), mink (KCNE1), & acid-sensitive TASK2 (KCNK5) & TASK3 (KCNK9). Western blots confirmed the presence of Kv1.5 & TASK2 proteins in sperm plasma membranes at similar (Kv1.5) or higher (TASK2) molecular weight than in somatic cells. Incubation in a different pH did not reveal acid sensitivity of volume regulation. Volume regulation of spermatozoa may involve novel voltage-gated & pH-sensitive potassium channels, which could be valuable targets for the development of a posttesticular male contraceptive.
Barfield J.P., et al. (2005) The Effects of Putative K+ Channel Blockers on Volume Regulation of Murine Spermatozoa. Biol reprod. PMID: 15673604
