View source for Chemistry:Pandinus imperator toxin (Pi4)

'''Pi4''' (α-KTx 6.4) is a short toxin from the scorpion ''[[Biology:Emperor scorpion|Pandinus imperator]]'' that blocks specific [[Biology:Voltage-gated potassium channel|potassium channels]].<ref name=":0">{{Cite journal|last1=Guijarro|first1=J. Iñaki|last2=M'Barek|first2=Sarrah|last3=Gómez-Lagunas|first3=Froylan|last4=Garnier|first4=Damien|last5=Rochat|first5=Hervé|last6=Sabatier|first6=Jean-Marc|last7=Possani|first7=Lourrival D.|last8=Delepierre|first8=Muriel|year=2003|title=Solution structure of Pi4, a short four-disulfide- bridged scorpion toxin specific of potassium channels|journal=Protein Science|volume=12|issue=9|pages=1844–1855|doi=10.1110/ps.03186703|pmid=12930984|pmc=2323982}}</ref><ref name=":1">{{Cite journal|last1=M'Barek|first1=Sarrah|last2=Mosbah|first2=Amor|last3=Sandoz|first3=Guillaume|last4=Fajloun|first4=Ziad|last5=Olamendi-Portugal|first5=Timoteo|last6=Rochat|first6=Hervé|last7=Sampieri|first7=François|last8=Guijarro|first8=J. Iñaki|last9=Mansuelle|first9=Pascal|year=2003|others=Muriel Delepierre, Michel De Waard, and Jean-Marc Sabatier|title=Synthesis and characterization of Pi4, a scorpion toxin from Pandinus imperator that acts on K + channels|journal=Eur. J. Biochem.|volume=270|issue=17|pages=3583–3592|doi=10.1046/j.1432-1033.2003.03743.x|pmid=12919322|doi-access=free}}</ref><ref name=":2">{{Cite journal|last1=Olamendi-Portugal|first1=Timoteo|last2=Gómez-Lagunas|first2=Froylan|last3=Gurrola|first3=Georgina B.|last4=Possani|first4=Lourival D.|year=1998|title=Two similar peptides from the venom of the scorpion pandinus imperator, one highly effective blocker and the other inactive on K+ channels|journal=Toxicon|volume=36|issue=5|pages=759–770|doi=10.1016/s0041-0101(97)00163-3|pmid=9655636}}</ref>
== Etymology ==
The name Pi4 is the fourth toxin isolated from the scorpion ''[[Biology:Emperor scorpion|Pandinus imperator]]'', from which Pi1, Pi2, Pi3, and Pi7 have also been isolated.<ref name=":2" />

== Chemistry ==
Pi4 is a [[Chemistry:Peptide|peptide]], which consists of 38 amino-acids with the following [[Biology:DNA sequencing|sequence]]:

IEAIRCGGSRDCYRPCQKRTGCPNAKCINKTCKCYGCS<ref name=":0" /><ref name=":3">{{Cite web|url=http://kaliumdb.org/|title=Kalium: Scorpion Toxins Active on Potassium Channels|website=kaliumdb.org|access-date=2016-10-09}}</ref>
 
It contains an α-helix and a β-sheet; it is stabilized by four [[Chemistry:Cysteine|cysteine]]-pairings that are [[Chemistry:Cross-link|crosslinked]] by four short [[Biology:Disulfide|disulfide bridges]]. The four disulfide bridges are characteristic for the α-KTX6 subfamily, while most other scorpion toxins contain only three disulfide bridges.<ref name=":0" /> The cysteines of Pi4 are paired in the following order: <sup>6</sup>C–<sup>27</sup>C; <sup>12</sup>C–<sup>32</sup>C; <sup>16</sup>C–<sup>34</sup>C; <sup>22</sup>C–<sup>37</sup>C.<ref name=":0" /><ref name=":3" />

Most disulfide bridges show a left-handed [[Chemistry:Conformational isomerism|conformation]], although in the disulfide bridge between <sup>22</sup>C–<sup>37</sup>C some variation is found. Only the disulfide bridge between <sup>6</sup>C–<sup>27</sup>C shows a right-handed conformation.<ref name=":0" />

== Target & Mode of action ==
Pi4 blocks different potassium channels, for instance, the [[Biology:Kv1.1|Shaker B]], K<sub>v</sub>1.2, and [[Biology:SK channel|SK]] potassium channels.

=== ''Shaker'' B channel ===

Pi4 binds to [[Biology:Shaker gene|Shaker B]] potassium channels, the Drosophila homologue of the voltage-gated potassium channel [[Biology:Kv1.1|K<sub>v</sub>1.1]].<ref name=":0" /> Pi4 reversibly blocks this channel with an [[Chemistry:IC50|IC<sub>50</sub>]] of 3.0 ± 2.2 nM.<ref name=":0" /><ref name=":1" />

A Pi4 peptide, synthesized with a different [[Biology:C-terminus|C-terminus]] than the natural Pi4 ([[Chemistry:Carboxylic acid|COO-]] instead of COH<sub>2</sub>N), shows the same binding characteristics as natural Pi4.<ref name=":0" /> This suggests that the C-terminus of the peptide Pi4 is not involved in the binding of Pi4 to the [[Biology:Shaker gene|Shaker B]] channel.<ref name=":0" />

The residues <sup>26</sup>K, <sup>28</sup>I, <sup>29</sup>N, <sup>33</sup>K, and <sup>35</sup>Y might be important for Pi4's interaction with [[Biology:Shaker gene|Shaker B]] channels,<ref name=":0" /> especially <sup>26</sup>K and <sup>35</sup>Y, which form a conserved dyad of a lysine and aromatic cluster in other potassium channel toxins.<ref>{{Cite journal|last1=Dauplais|first1=Marc|last2=Lecoq|first2=Alain|last3=Song|first3=Jianxing|last4=Cotton|first4=Joël|last5=Jamin|first5=Nadège|last6=Gilquin|first6=Bernard|last7=Roumestand|first7=Christian|last8=Vita|first8=Claudio|last9=Medeiros|first9=Cleane L. C. de|date=1997-02-14|title=On the Convergent Evolution of Animal Toxins CONSERVATION OF A DIAD OF FUNCTIONAL RESIDUES IN POTASSIUM CHANNEL-BLOCKING TOXINS WITH UNRELATED STRUCTURES|journal=Journal of Biological Chemistry|language=en|volume=272|issue=7|pages=4302–4309|doi=10.1074/jbc.272.7.4302|issn=0021-9258|pmid=9020148|doi-access=free}}</ref> It has been suggested that the positive charge of the lysine mimicks a potassium ion and enters the pore of the potassium channel,<ref>{{Cite journal|last1=Goldstein|first1=S.A.|last2=Miller|first2=C.|title=Mechanism of charybdotoxin block of a voltage-gated K+ channel|journal=Biophysical Journal|volume=65|issue=4|pages=1613–1619|doi=10.1016/s0006-3495(93)81200-1|pmid=7506068|pmc=1225887|year=1993|bibcode=1993BpJ....65.1613G}}</ref><ref>{{Cite journal|last1=Giangiacomo|first1=Kathleen M.|last2=Garcia|first2=Maria L.|last3=McManus|first3=Owen B.|date=1992-07-01|title=Mechanism of iberiotoxin block of the large-conductance calcium-activated potassium channel from bovine aortic smooth muscle|journal=Biochemistry|volume=31|issue=29|pages=6719–6727|doi=10.1021/bi00144a011|pmid=1379069|issn=0006-2960}}</ref><ref>{{Cite journal|last1=Park|first1=Chul-Seung|last2=Miller|first2=Christopher|title=Interaction of charybdotoxin with permeant ions inside the pore of a K+ channel|journal=Neuron|volume=9|issue=2|pages=307–313|doi=10.1016/0896-6273(92)90169-e|pmid=1379820|year=1992|s2cid=43596648}}</ref> hence occluding the pore opening and inhibiting the ion flux.

=== Kv1.2 channel ===

Pi4 blocks the [[Biology:Voltage-gated potassium channel|voltage-gated potassium channel]] K<sub>v</sub>1.2.<ref name=":1" /> at low concentrations ([[Chemistry:IC50|IC<sub>50</sub>]] 8.0 ± 5 pM).<ref name=":1" /> No significant effects have been observed on Kv1.1 and Kv1.3 channels at concentrations up to 10&nbsp;μm.<ref name=":1" />

In the binding of the peptide Pi4 to the K<sub>v</sub>1.2 channel, the β-sheet structure is thought to play an important role. First, the residue <sup>35</sup>Y, located in the β-sheet structure, tightly interacts via electrostatic forces with the aromatic cluster of Kv1.2 channels (<sup>344</sup>W, <sup>345</sup>W and <sup>355</sup>Y).<ref name=":1" /> Second, the residue <sup>26</sup>K becomes stabilized by the four carbonyl oxygen atoms located in the channel of pore formed by four Kv1.2 α-subunits  (<sup>357</sup>D).<ref name=":1" /> Finally, the four <sup>332</sup>Q residues of the four α-subunits of Kv1.2 channels interact via salt bridges with four subunits of the toxin ring (composed of <sup>10</sup>R, <sup>19</sup>R, <sup>30</sup>K, <sup>33</sup>K).<ref name=":1" />

=== SK-channel ===

Furthermore, the Pi4 binds to [[Biology:SK channel|SK channel]]s, small conductance Ca<sup>2+</sup>-activated potassium channels.<ref name=":1" /> Pi4 competes with [[Chemistry:Apamin|apamin]], another [[Biology:SK channel|SK-channel]] toxin. IC<sub>50</sub> is 0.5 ± 0.2 μM.<ref name=":1" />

== Toxicity ==
Scorpion venoms can be toxic for mammals, insects, and crustaceans.<ref name=":0" /> Pi4 is lethal in mice upon injection in the [[Biology:Ventricular system|ventricular system]] of the brain at and LD<sub>50</sub> value of 0.2 &nbsp;μg/mouse.<ref name=":1" />

== References ==
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[[Category:Ion channel toxins]]

{{Sourceattribution|Pandinus imperator toxin (Pi4)}}