VHH Nanobody Versatility against Pentameric Ligand-Gated Ion Channels

Pentameric ligand-gated ion channels provide rapid chemical-electrical signal transmission between cells in the central and peripheral nervous system. Their dysfunction is associated with many nervous system disorders. They are composed of five identical (homomeric receptors) or homologous (heteromeric receptors) subunits. VHH nanobodies, or single-chain antibodies, are the variable domain, VH_H, of antibodies that are composed of the heavy chain only from camelids. Their unique structure results in many specific biochemical and biophysical properties that make them an excellent alternative to conventional antibodies. This Perspective explores the published VHH nanobodies which have been isolated against pentameric ligand-gated ion channel subfamilies. It outlines the genetic and chemical modifications available to alter nanobody function. An assessment of the available functional and structural data indicate that it is feasible to create therapeutic agents and impart, through their modification, a given desired modulatory effect of its target receptor for current stoichiometric-specific VHH nanobodies.