Resurgent current and voltage sensor trapping enhanced activation by a beta-scorpion toxin solely in Nav1.6 channel. Significance in mice Purkinje neurons.
Resurgent currents are functionally crucial in sustaining the high frequency firing of cerebellar Purkinje neurons expressing Na(v)1.6 channels. Beta-scorpion toxins, such as CssIV, induce a left shift in the voltage-dependent activation of Na(v)1.2 channels by "trapping" the IIS4 voltage sensor segment. We found that the dangerous Cn2 beta-scorpion peptide induces both the left shift voltage-dependent activation and a transient resurgent current only in human Na(v)1.6 channels (among 1.1-1.7), whereas CssIV did not induce the resurgent current. Cn2 also produced both actions in mouse Purkinje cells. These findings suggest that only distinct beta-toxins produce resurgent currents. We suggest that the novel and unique selectivity of Cn2 could make it a model drug to replace deep brain stimulation of the subthalamic nucleus in patients with Parkinson disease.
Schiavon
Emanuele
E
Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan 20126, Italy.
Sacco
Tiziana
T
Cassulini
Rita Restano
RR
Gurrola
Georgina
G
Tempia
Filippo
F
Possani
Lourival D
LD
Wanke
Enzo
E
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D007668:Kidney; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D011487:Protein Conformation; D011689:Purkinje Cells / Q000502:physiology*; D012604:Scorpion Venoms / Q000302:isolation & purification / Q000633:toxicity*; D012605:Scorpions; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000633:toxicity
D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C100681:SCN8A protein, human; C491046:Scn8a protein, mouse; D012604:Scorpion Venoms; D015222:Sodium Channels; D013779:Tetrodotoxin