Olfactory transduction is the process by which olfactory sensory neurons (OSNs) transform odor information into neuronal electrical signals. Over the past two and a half decades, extensive investigations have led to the elucidation of a core transduction pathway in vertebrate OSNs. However, the processes that regulate transduction to allow for proper sensitivity and response kinetics are not well understood. Calcium is a key olfactory transduction regulator. Calcium enters the sensory cilium through the olfactory cyclic nucleotide-gated (CNG) channel during the odor response, amplifies OSN depolarization, and also negatively regulating several olfactory transduction components. This negative regulation governs OSN adaptation--a phenomenon manifested as reduced sensitivity upon sustained or repeated stimulation. In this proposal, we propose to take advantage of multiple genetically modified mouse strains that we generated to: 1) investigate the integration of multiple Ca2+-dependent feedback mechanisms in OSN adaptation (Aim 1);and 2) investigate the role of negative regulatory mechanisms, which function in termination and adaptation, in setting OSN sensitivity at rest (Aim 2). Electrophysiological analysis, at the level of intact olfactory epithelium and the isolated single cell level, will be conducted on mice carrying double or triple mutations for calcium-dependent feedback mechanisms (Aim 1) as well as on mice that lack a calcium-dependent feedback mechanism and also lack efficient calcium extrusion (Aim 2). The long-term goal of this proposal is to elucidate the molecular mechanisms underlying olfaction. The proposed investigation will lead to a better understanding of how OSNs encode the intensity and temporal features of odor stimulations by regulating sensitivity and response kinetics. The knowledge gained from the proposed research will enhance our understanding of normal olfactory function and olfactory dysfunctions.

Public Health Relevance

The sense of smell is important for locating food, mates, avoiding danger, and enhancing the quality of life. Despite the fact that many of the molecular components that allow us to smell are known, the mechanisms governing the sensitivity and response speed are not well understood. The proposed research will enhance our understanding of the basic responses of the olfactory system, which will give us insight into the genetic and physiological causes of smell disorders.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Arts and Sciences
United States
Zip Code
Parry, David A; Poulter, James A; Logan, Clare V et al. (2013) Identification of mutations in SLC24A4, encoding a potassium-dependent sodium/calcium exchanger, as a cause of amelogenesis imperfecta. Am J Hum Genet 92:307-12
Ryu, Yun Kyoung; Collins, Sarah Ellen; Ho, Hsin-Yi Henry et al. (2013) An autocrine Wnt5a-Ror signaling loop mediates sympathetic target innervation. Dev Biol 377:79-89
Ponissery Saidu, Samsudeen; Stephan, Aaron B; Talaga, Anna K et al. (2013) Channel properties of the splicing isoforms of the olfactory calcium-activated chloride channel Anoctamin 2. J Gen Physiol 141:691-703
Stephan, Aaron B; Tobochnik, Steven; Dibattista, Michele et al. (2012) The Na(+)/Ca(2+) exchanger NCKX4 governs termination and adaptation of the mammalian olfactory response. Nat Neurosci 15:131-7
Reisert, Johannes; Zhao, Haiqing (2011) Perspectives on: information and coding in mammalian sensory physiology: response kinetics of olfactory receptor neurons and the implications in olfactory coding. J Gen Physiol 138:303-10
Cygnar, Katherine D; Stephan, Aaron B; Zhao, Haiqing (2010) Analyzing responses of mouse olfactory sensory neurons using the air-phase electroolfactogram recording. J Vis Exp :
Cygnar, Katherine D; Zhao, Haiqing (2009) Phosphodiesterase 1C is dispensable for rapid response termination of olfactory sensory neurons. Nat Neurosci 12:454-62
Stephan, Aaron B; Shum, Eleen Y; Hirsh, Sarah et al. (2009) ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification. Proc Natl Acad Sci U S A 106:11776-81
Song, Yijun; Cygnar, Katherine D; Sagdullaev, Botir et al. (2008) Olfactory CNG channel desensitization by Ca2+/CaM via the B1b subunit affects response termination but not sensitivity to recurring stimulation. Neuron 58:374-86