Tethering toxins and peptide ligands for modulation of neuronal function

Abstract

Tethering genetically encoded peptide toxins or ligands close to their point of activity at the cell plasma membrane provides a new approach to the study of cell networks and neuronal circuits, as it allows selective targeting of specific cell populations, enhances the working concentration of the ligand or blocker peptide, and permits the engineering of a large variety of t-peptides (e.g., including use of fluorescent markers, viral vectors and point mutation variants). This review describes the development of tethered toxins and peptides derived from the identification of the cell surface nAChR modulator lynx1, the existence of related endogenous cell surface modulators of nAChR and AMPA receptors, and the application of the t-toxin and t-neuropeptide technology to the dissection of neuronal circuits in metazoans.

Mapping and Cracking Sensorimotor Circuits in Genetic Model Organisms

“…Having independent control over each synaptic input to a cell while providing a stimulus and monitoring behavior would allow one to attribute particular behavioral and computational roles to specific synapses. While such tools are not broadly available, exciting steps in this direction are underway (Ibanez-Tallon and Nitabach, 2012; Levitz et al, 2013; Szobota and Isacoff, 2010). More modestly, one can envision artificially controlling the activity of a neuron, reproducing exactly its native temporal activity and statistics in the context of a particular stimulus and then deviating from it.…”

The Genetic Analysis of Functional Connectomics in Drosophila

“…This dominant-negative strategy has been applied to other K + channels, such as Eag and Shaw (Broughton et al ., 2004; Hodge et al ., 2005), as well as to the Na + /K + ATPase (Sun et al ., 2001; Parisky et a l., 2008). Membrane-tethered toxins (t-toxins) provide a valuable alternative for cell-autonomous modulation of channels and receptors (reviewed in Ibañez-Tallon and Nitabach, 2012). For example, four spider toxins tethered to membrane with a glycosylphosphatidylinositol (GPI) anchor have each been shown to block their previously identified targets, including Ca 2+ , K + and Na + channels (Wu et al ., 2008).…”

Peptide Neuromodulation in Invertebrate Model Systems

“…When small LNv express a gene encoding a “tethered PDF”, their resting membrane potential is depolarized even when they are decoupled from neuronal signaling networks by bath application of tetrodotoxin, which block Na + -dependent action potentials (Choi et al, 2012), suggesting that PDF generates electrogenic responses in PDF-R-expressing neurons. In the tethered peptide design, the PDF peptide sequence is fused by a linker region to a membrane-integral GPI anchor; the PDF moiety is located extracellularly and is able to interact with and activate cognate receptors expressed by the same cell (Choi et al, 2009) (Fortin et al, 2009; Ibanez-Tallon and Nitabach, 2012). …”