Shaping smell: chloride currents dictate the kinetics of olfactory transduction

Abstract

The sensory modalities are anatomically, biochemically and physiologically organized to detect and perceive vanishingly small quantities of environmental stimulus energies. The visual system's sensitivity is sufficient to detect single photons, while in the olfactory system, odorants can be detected in the range of parts per billion. To achieve such sensitivity, both systems have evolved biochemical amplifiers of their respective transduction currents.

Olfactory transduction begins when volatilized odorant molecules bind to olfactory receptor (OR) proteins on the cilia of olfactory sensory neurons. ORs are G-protein coupled receptors, and their activation stimulates the catalytic activity of adenylyl cyclase III, increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP). cAMP then binds to cation nonselective cyclic nucleotide-gated ion channels, allowing for an influx of sodium and calcium ions, the initial components of the olfactory transduction current (Fig. 1). In the final step, fluxed calcium ions activate a calcium-activated chloride channel (TMEM16B; Lowe & Gold, 1993). In the unusual case of olfactory sensory neurons, the chloride gradient favours the intracellular compartment and thus negatively charged chloride ions are effluxed, and the overall transduction current is amplified.

While amplification of sensory transduction currents provides a mechanism to ensure the detection of environmental stimuli, the trade-off is over-amplification and output saturation as stimuli become more abundant. The visual and olfactory systems alike have evolved mechanisms to implement physiological and perceptual adaptation to counter this. However, in the olfactory system, the biochemical and physiological basis of adaptation has been elusive.

In this edition of the Journal of Physiology, Reisert and colleagues (Reisert et al., 2024) demonstrate the dual role of the calcium-activated chloride channel, TMEM16B, in amplifying olfactory transduction currents and controlling adaptation. Using ex vivo and dissociated preparations of the olfactory epithelium in Tmem16b knockout mice, they devised a stimulation paradigm to mimic the rhymical nature of the respiration cycle while recording action potentials in individual olfactory sensory neurons. Two separate frequencies were selected to mimic passive breathing (2 Hz) and active sniffing (5 Hz). At each frequency, sensory neurons from wild-type mice adapted across stimulations – fewer action potentials were generated on each successive stimulation. When recording from olfactory sensory neurons lacking TMEM16B, adaptation was markedly less at both stimulation frequencies. Furthermore, the degree of adaptation was dependent on the odorant concentration in wild-type sensory neurons, while concentration dependence was less apparent in Tmem16b knockout recordings.

In addition to implicating TMEM16B in adapting olfactory sensory neuron output, their study confirms its paradoxical role in the olfactory transduction cascade. Despite amplifying transduction currents, TMEM16B ultimately limits cellular output. The massive membrane depolarizations induced by the current carried by TMEM16B push voltage-gated sodium channels into their voltage-inactivation state, thereby limiting the number of action potentials generated (Pietra et al., 2016; Zak et al., 2018). The emerging view of TMEM16B in olfactory transduction is that it functions to sparsen input from the peripheral olfactory system to the brain.

While Reisert et al. demonstrate that TMEM16B contributes to adaptation, other biochemical mechanisms likely also contribute. For example, cyclic nucleotide-gated channels contain a calmodulin domain that decreases the conducting properties of the channel when bound to free calcium. However, it is worth noting that the expression of calmodulin is unaffected in Tmem16b knockout mice (Li et al., 2018); therefore, it appears that the calmodulin domain may be insufficient to control adaptation independent of TMEM16B. How these two mechanisms, respectively and collectively, contribute to peripheral adaptation has yet to be explored.

Their findings also raise new questions that can addressed using in vivo systems. For instance, does TMEM16B contribute to olfactory sensory neuron respiratory phase locking? Discretizing sensory neuron activity within the context of the respiration cycle is likely to be essential for comparing stimulus dynamics in the temporal domain. Without adaptation, the activity generated by each independent sniff may blend and obscure comparisons between sampling events. A second consideration is how downstream circuits in the olfactory processing hierarchy may compensate for the lack of adaptation. Recent behavioural studies demonstrate that Tmem16b knockout mice can detect and evaluate olfactory stimuli, yet there are differences with respect to wild-type mice on fine-scale olfactory-guided behaviours. How central circuits handle reformatted peripheral inputs will be critical for understanding the behavioural and perceptual significance of adaptation.