INTERACTIONS OF DELTA-CONOTOXINS WITH ALKALOID NEUROTOXINS REVEAL DIFFERENCES BETWEEN THE SILENT AND EFFECTIVE BINDING-SITES ON VOLTAGE-SENSITIVE SODIUM-CHANNELS

The delta-conotoxin-TxVIA from Conus textile (delta TxVIA) is a mollus k-specific conotoxin that slows sodium channel inactivation exclusivel y in mollusk neuronal membranes but reveals high-affinity binding to b oth mollusk (effective binding) and rat brain (silent binding) neurona l membranes, despite not having any toxic effect in vertebrates in viv o and in vitro. Using binding studies with radioactive delta TxVIA we demonstrate that a different mollusk-specific conotoxin, delta-conotox in-GmVIA from the venom of Conus gloriamaris, possesses ''silent'' and effective binding properties in rat brain and mollusk sodium channels , respectively. Binding studies and electrophysiological tests with bo th vertebrate muscle and insect neuronal preparations have indicated t hat the silent binding sites of delta TxVIA are highly conserved in a wide range of distinct vertebrate and insect sodium channels. Direct p robing of receptor site 2 by a tritiated derivative of batrachotoxin ( [H-3]BTX-B) revealed that [H-3]BTX-B binding in mollusk sodium channel s is of high affinity with no addition of enhancing ligands, unlike [H -3]BTX-B binding in rat brain. In contrast to the negative allosteric modulation of delta TxVIA binding by veratridine, delta TxVIA is not a ble to affect the binding of [H-3]BTX-B in mollusk neuronal membranes but reduces [H-3]BTX-B binding in rat brain in the presence of alpha-s corpion toxins. The latter finding indicates the existence of a pharma cological distinction between the silent and effective binding sites o f delta TxVIA and points out possible functionally important structura l differences between molluscan and rat brain sodium channels.