What is so special about smell? Olfaction as a model system in neurobiology

Abstract

Neurobiology studies mechanisms of cell signalling. A key question is how cells recognise specific signals. In this context, olfaction has become an important experimental system over the past 25 years. The olfactory system responds to an array of structurally diverse stimuli. The discovery of the olfactory receptors (ORs), recognising these stimuli, established the olfactory pathway as part of a greater group of signalling mechanisms mediated by G-protein-coupled receptors (GPCRs). GPCRs are the largest protein family in the mammalian genome and involved in numerous fundamental physiological processes. The OR family exhibits two characteristics that make them an excellent model system to understand GPCRs: its size and the structural diversity of its members. Research on the OR binding site investigates what amino acid sequences determine the receptor-binding capacity. This promises a better understanding of how the basic genetic makeup of GPCRs relates to their diversification in ligand-binding capacities.

The role of metals in mammalian olfaction of low molecular weight organosulfur compounds

“…Molecular recognition instead occurs through the pattern of response from hundreds of different types of olfactory receptor epithelia cells…” This pattern of response is, in turn, based on a range of intermolecular interactions connecting the odorant with the receptor over a continuum from the stronger ligand coordination involving metals, to electrostatic ion–ion and proton acid–base interactions, hydrogen bonding, halogen bonding, charge-transfer and π–π molecular complexation, dipolar and multipolar interactions, and weaker van der Waals interactions. 28a While there is also a dynamic aspect to odorant-OR interaction (the odorants must rapidly separate from the ORs to allow real-time sensing of changes in odor nature and concentration), stronger interactions favor increased sensitivity and greater chemical specificity. Recent work should be noted here by Kobilka and coworkers on GPCR dynamic processes for signaling by β 2 -adrenergic and μ-opiod receptors (β 2 AR and μORs, respective-ly), 28b-d given that there should be similarities in behavior of olfactory and non-olfactory GPCRs in view of their extensive morphological similarities, as well as the already noted 7a occur-rence of ORs in non-olfactory tissues.…”

“…28a While there is also a dynamic aspect to odorant-OR interaction (the odorants must rapidly separate from the ORs to allow real-time sensing of changes in odor nature and concentration), stronger interactions favor increased sensitivity and greater chemical specificity. Recent work should be noted here by Kobilka and coworkers on GPCR dynamic processes for signaling by β 2 -adrenergic and μ-opiod receptors (β 2 AR and μORs, respective-ly), 28b-d given that there should be similarities in behavior of olfactory and non-olfactory GPCRs in view of their extensive morphological similarities, as well as the already noted 7a occur-rence of ORs in non-olfactory tissues. Indeed, it has been asserted that ORs are model systems for GPCRs within neurobiology.…”

“…Indeed, as early as 1940, Pauling and Delbrück noted that interacting biomolecules “must have complementary surfaces, like die and coin, and also a complementary distribution of active groups.” 28f …”

Quantum effects in biology: golden rule in enzymes, olfaction, photosynthesis and magnetodetection

“…[45] copyright Proceedings of National Academy of Sciences, USA. Also shown are dose-response curves of OR5AN1 plots for (1) cyclopentadecanone and (4) muscone and the scatter plots with 96% confidence interval log EC 50 values, showing there is no differentiation between isotopes that is statistically significant [45].…”

“…Calculating the electronic coupling for initial and final wave functions without any structural information would constitute very involved guess-work, given structural fluctuations on the picosecond time scale and sub-ångström distances may substantially affect any quantum process. However, recent studies have advanced knowledge of the binding site [50] and new research is emerging to show that biological IETS may play a role in neuroreceptors [51]. So let the notion of phonon-assisted electron tunnelling (as a signalling mechanism) be emphasized and not ignored, if not a role in olfaction, but perhaps in other systems in biology that rely upon ligand-receptor activation.…”