Voltage-gated sodium channel isoform-specific effects of pompilidotoxins.
Pompilidotoxins (PMTXs, alpha and beta) are small peptides consisting of 13 amino acids purified from the venom of the solitary wasps Anoplius samariensis (alpha-PMTX) and Batozonellus maculifrons (beta-PMTX). They are known to facilitate synaptic transmission in the lobster neuromuscular junction, and to slow sodium channel inactivation. By using beta-PMTX, alpha-PMTX and four synthetic analogs with amino acid changes, we conducted a thorough study of the effects of PMTXs on sodium current inactivation in seven mammalian voltage-gated sodium channel (VGSC) isoforms and one insect VGSC (DmNa(v)1). By evaluating three components of which the inactivating current is composed (fast, slow and steady-state components), we could distinguish three distinct groups of PMTX effects. The first group concerned the insect and Na(v)1.6 channels, which showed a large increase in the steady-state current component without any increase in the slow component. Moreover, the dose-dependent increase in this steady-state component was correlated with the dose-dependent decrease in the fast component. A second group of effects concerned the Na(v)1.1, Na(v)1.2, Na(v)1.3 and Na(v)1.7 isoforms, which responded with a large increase in the slow component, and showed only a small steady-state component. As with the first group of effects, the slow component was dose-dependent and correlated with the decrease in the fast component. Finally, a third group of effects concerned Na(v)1.4 and Na(v)1.5, which did not show any change in the slow or steady-state component. These data shed light on the complex and intriguing behavior of VGSCs in response to PMTXs, helping us to better understand the molecular determinants explaining isoform-specific effects.
Schiavon
Emanuele
E
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
Stevens
Marijke
M
Zaharenko
André J
AJ
Konno
Katsuhiro
K
Tytgat
Jan
J
Wanke
Enzo
E
D000595:Amino Acid Sequence; D000818:Animals; D000997:Antivenins / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019476:Insect Proteins / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000737:chemistry / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects*; D014862:Wasp Venoms / Q000737:chemistry / Q000494:pharmacology*
D000997:Antivenins; D019476:Insect Proteins; D010455:Peptides; D020033:Protein Isoforms; D015222:Sodium Channels; D014862:Wasp Venoms; C115328:pompilidotoxin alpha; C115329:pompilidotoxin beta