Mammalian olfactory signal transduction: an update

Olfactory signal transduction is the series of events for the transformation of a chemical signal, an odorant, in an electric one that is then sent to the brain. The very first step consists of the binding of odorant molecules to olfactory receptors, located on the cilia of olfactory sensory neurons (OSNs). This triggers an enzymatic cascade that leads to the increase of intraciliary cAMP followed by ion channels opening: first, directly gated by cAMP, the cyclic nucleotide gated (CNG) channels and then the calcium activated chloride channels (CaCC). By the mid 90’ the picture was almost complete. Indeed, all the elements involved in olfactory transduction were known, bar one: the identity of the CaCC. Although the Cl- current has largely been characterized biophysically, the molecular identity and physiological role of the CaCC were largely elusive. Despite several attempts, the olfactory CaCC identity has been a mystery till the discovery (in other cell types) of a new family of chloride channels: the TMEM16. In 2009 it was demonstrated that one member of this family, TMEM16b, was indeed the olfactory native channel. Surprisingly, it was shown that TMEM16B has a limited to possibly no role in olfactory physiology and behavior. What is the role of TMEM16B, then? We decided to re-examine the question and found that mice lacking TMEM16B have an impaired odor-guided food finding behavior and their OSNs have altered spontaneous and also evoked action potential firing. In summary, the overall understanding of olfactory signal transduction needs to be updated to include the functions for the long time unknown and elusive calcium activated chloride channel, TMEM16B.