Neurotoxic peptides and proteins: biomarkers for screening and identifying ion channel subtypes in healthy/diseased conditions and for drug design

Abstract

Cys-loop receptors comprising nicotinic acetylcholine receptors (nAChRs), glycine-, ionotropic GABA and serotonin receptors exist as several subtypes differing in localization and role in normal functioning/pathologies. Contrary to antibodies, their identification is more efficient with neurotoxic peptides and proteins from animal venoms, highly selectivity for a particular receptor subtype. Naturally-occurring neurotoxins are used in electrophysiology, while their radioactive/fluorescent derivatives help to measure the receptor subtypes at normal state and diseases. Such measurements are important, for example, for α4β2 nAChRs involved in nicotine addiction, for α7 neuronal nAChRs implicated in β-amyloid peptide binding and for “non-neuronal” α7 nAChR regulating anti-inflammatory response and lung cancer growth. X-ray analysis of the neurotoxin complexes with the receptor models shed light on the binding sites and on possible functional effects of certain disease-associated mutations. Neurotoxins give hints for new drugs or become drugs themselves: like a strong analgesic ω-conotoxin (Prialt) blocking one Ca2+ channel subtype. Several α-conotoxins blocking α9/α10 nAChRs are considered as possible analgesics emphasizing that fundamental research of ligand-receptor interactions is important for solving practical medical tasks. Our recent work on (1) nAChRs and other Cys-loop receptors will be illustrated with novel high-affinity α-conotoxins, (2) snake venom α-neurotoxins (3) human endogenous proteins that have the same three-finger folding as α-neurotoxins and regulate the nAChR activities.