Odorant-Receptor Interaction - Bioelectronic Nose: Integration of Biotechnology and Nanotechnology - page 74

Fig. 4.3 A model for copper ion involvement in odorant-receptor interaction. For copper-coor-
dinating odorants, such as the one shown with a thiol and a thioether group, the copper ion binds
to the ligand, resulting in a conformation change in the ligand, followed by binding of the copper
ion-ligand complex to the OR. (Adapted with permission from [ 59 ]. Copyright 2012, PNAS )
[ 58 ] revisited the subject and proposed that ORs may function as metalloproteins.
They found that the synthetic pentapeptide HACKE, corresponding to a con-
served sequence in the extracellular loop of human ORs, has high affinity for
copper and zinc ions and therefore may form the basis for sensitive detection
of certain odorant molecules with intense smells, including thiols, amines, and
carboxylic acids [ 58 ].
A recent study from our group showed that copper ion plays a key role in the
activation of MOR244-3 [ 59 ]. Using the HEK293T cell-based OR expression
system, we found that copper ion specifically enhanced the mouse OR's response
to a strong-smelling semiochemical, named (methylthio)methanethiol [ 60 ], and
structurally-related sulfur-containing compounds, as well as a few unrelated met-
al-coordinating compounds. The results were replicated using electrophysiologi-
cal recordings on mouse septal organ neurons, where MOR244-3 is abundantly
expressed [ 61 ]. Given the above observations, it is probable that under in vivo con-
ditions, copper may be present in the mucus to exert its function. Indeed, it was
found that the total copper concentration of mouse nasal mucus is around 40 μM,
similar to that used in the in vitro study [ 59 ]. Based on these findings, we proposed
a model for OR activation involving copper ion as a cofactor with the copper ion
binding to the ligand for subsequent binding of the metal-odorant complex to the
OR (Fig. 4.3 ). In contrast, in a separate study, Viswaprakash et al. [ 62 ] demonstrat-
ed that Zn 2+ ion decreased the odorant response in rat olfactory epithelium while
a small amount of zinc nanoparticles strongly increased the odorant response in a
dose-dependent manner. Further work needs to be carried out to explain the dif-
ferential effects between the neutral (nanoparticle) and ionic forms of zinc. Though
both studies mentioned above showed that metal ions could modulate the activation
of ORs, important aspects of the metal involvement remain unresolved, including
OR active site identity, the binding mode of metal ions (and neutral metal atoms)
alongside metal-coordinating ligands, unifying structural features defining metal-
requiring ORs and ligands, if any, and finally, an assessment of the prevalence of the
metal ion requirement in the mammalian OR repertoire. Answers to these questions
should facilitate the elucidation of the exact role of metal ions in OR activation.