Ca ²⁺ -activated Cl ⁻ current ensures robust and reliable signal amplification in vertebrate olfactory receptor neurons

Abstract

Activation of most primary sensory neurons results in transduction currents that are carried by cations. One notable exception is the vertebrate olfactory receptor neuron (ORN), where the transduction current is carried largely by the anion Cl−. However, it remains unclear why ORNs use an anionic current for signal amplification. We have sought to provide clarification on this topic by studying the so far neglected dynamics of Na+, Ca2+, K+, and Cl− in the small space of olfactory cilia during an odorant response. Using computational modeling and simulations we compared the outcomes of signal amplification based on either Cl− or Na+ currents. We found that amplification produced by Na+ influx instead of a Cl− efflux is problematic for several reasons: First, the Na+ current amplitude varies greatly, depending on mucosal ion concentration changes. Second, a Na+ current leads to a large increase in the ciliary Na+ concentration during an odorant response. This increase inhibits and even reverses Ca2+ clearance by Na+/Ca2+/K+ exchange, which is essential for response termination. Finally, a Na+ current increases the ciliary osmotic pressure, which could cause swelling to damage the cilia. By contrast, a transduction pathway based on Cl− efflux circumvents these problems and renders the odorant response robust and reliable.

An update on anatomy and function of the teleost olfactory system

“…In ciliated ORNs of teleosts, as in those of higher vertebrates (Buck & Axel, 1991), the alpha subunit of the G α olf protein triggers the activation of the enzyme adenylate cyclase, generating an increase in cyclic AMP (cAMP) that functions as a second messenger (Hansen et al, 2003; Schmachtenberg & Bacigalupo, 2004). cAMP causes the activation of cationic cyclic nucleotide-gated channels (CNGCs), allowing the influx of sodium and to a lesser extent of calcium, which depolarizes the cell membrane directly and by an amplifying effect, through the activation of nearby calcium-dependent chloride channels (Kurahashi & Yau, 1994; Reisert & Reingruber, 2019). In addition, calcium contributes to the termination of the response through an adaptive reduction of the sensitivity of CNGCs to cyclic nucleotides by means of calcium-calmodulin activation, until intracellular calcium levels return to pre-stimulation levels mainly by action of the sodium-calcium exchanger (Matthews & Reisert, 2003).…”

Modulation of olfactory signal detection in the olfactory epithelium: focus on the internal and external environment, and the emerging role of the immune system

“…Lane and collaborators propose that the chronic presence of proinflammatory cytokines could reduce EOG responses by establishing a desensitized state that leads to reduced neuronal firing (Lane et al 2010). Such an importance for a finely regulated spatial and temporal dynamics of calcium influx in the modulation of olfactory transduction has been confirmed later (Reisert and Reingruber 2019). Our group recently focused on IL-17C, an interleukin playing a crucial role in mucosal areas and whose neuromodulatory properties are well-described in the peripheral nervous system (Peng et al 2017).…”

“…Genetic tools offer another experimental approach to examine activity-dependent survival of OSNs. In mice, Zhao and Reed (2001) took advantage of the X chromosome location of the OCNC1 gene, one of the key genes in olfactory transduction, encoding an essential subunit of the olfactory cyclic nucleotide gated channel, which is essential for the depolarization of OSNs (Reisert and Reingruber 2019). In their study, Zhao and Reed replaced OCNC1 with the ß-galactosidase reporter gene, allowing a direct visualization of OCNC1-deficient olfactory neurons and their projections.…”

TMEM16A calcium-activated chloride currents in supporting cells of the mouse olfactory epithelium

“…The mucus composition is fundamental to maintain the ionic environment necessary for olfactory transduction. Indeed, the binding of odorant molecules to odorant receptors in the cilia of olfactory sensory neurons leads to a transduction cascade that includes the activation of CNG channels and the Ca 2+ -activated Cl − channels TMEM16B, whose function depends on the Cl − electrochemical gradient between the mucus and the intraciliary compartment (Pifferi et al, 2009; Stephan et al, 2009; Billig et al, 2011; Pietra et al, 2016; Dibattista et al, 2017; Neureither et al, 2017; Li et al, 2018; Zak et al, 2018; Reisert and Reingruber, 2019). Thus, the Cl − concentration regulated by TMEM16A would affect the TMEM16B-mediated current, modifying the odorant response of the olfactory sensory neurons.…”