Link Between Pain and Olfaction in an Inherited Sodium Channelopathy

Figure 1. Schematic drawings of olfactory sensory neuron (OSN) function. A, Electrical activity in canonical mammalian OSNs constitutes a generator potential (a graded membrane depolarization caused by the activity of the primary signal transduction cascade, as shown in part B) and action potentials that propagate along the olfactory axons toward the olfactory bulb. B, Schematic drawing of the primary olfactory signal transduction cascade localized in the OSN cilia. Binding of an odor molecule to an odor receptor (OR) triggers activation of adenylyl cyclase type 3 (Adcy3 [ACIII in the schematic]) via the heterotrimeric G protein G_olf (α subunit encoded by Gnal). This process results in the formation of cyclic adenosine monophosphate (cAMP), which in turn activates a calcium ion (Ca²⁺)–permeable, cyclic nucleotide–gated (CNG) cation channel (primary subunit encoded by Cnga2). Entry of Ca²⁺ through this channel triggers a Ca²⁺-activated chloride (Cl⁻) channel, encoded by Ano2. In mice, targeted disruption of Gnal, Adcy3, or Cnga2 leads to general anosmia. Disruption of Ano2 is dispensable for olfaction. C, Schematic view showing the anatomical organization of the olfactory system from the OSNs in the olfactory epithelium to the first synapse in the glomeruli of the olfactory bulb. The OSN axons form cranial nerve I. Mitral cell axons form the lateral olfactory tract, which transmits information from the olfactory bulb to cortical areas. Axons from OSNs expressing the same OR terminate in the same glomerulus (indicated by color coding). ATP indicates adenosine triphosphate; Na⁺, sodium ion.

Figure 2. Schematic model (based on original results published by Weiss et al²¹) depicting the presynaptic localization of voltage-gated sodium channel Na_v1.7 at the first synapse in the olfactory neural pathway and its critical role in transmitter release. Loss of Na_v1.7 function in olfactory sensory neurons leads to a loss of postsynaptic currents in mitral cells, indicating a lack of transmitter release at this synapse. The molecular identity of voltage-gated calcium ion channels (Ca_v) underlying synaptic release is not yet known. NS indicates nerve stimulation; cNav1.7^−/−, conditional homozygous deletion of Nav1.7; and cNav1.7^+/−, conditional heterozygous deletion of Nav1.7.