Olfactory Signal Transduction
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Olfactory Signal Transduction
The olfactory system is a very efficient biological setup capable of odor information processing with neural signals. The mammalian olfactory system can recognize and discriminate a large number of different odorant molecules. The detection of chemically distinct odorants presumably results from the association of odorous ligands with specific receptors on OSNs (Olfactory Sensory Neurons). As a chemical sensor, the olfactory system detects food and influences social and sexual behavior. Activation occurs when odiferous molecules come in contact with specialized processes known as the olfactory vesicles. Within the nasal cavity, the turbinates or nasal conchae serve to direct the inspired air toward the olfactory epithelium in the upper posterior region. This area (only a few centimeters wide) contains more than 100 million OLFR (Olfactory (or Odorant) Receptor) cells. These specialized epithelial cells give rise to the olfactory vesicles containing cilia, which serve as sites of stimulus transduction. To address the problem of olfactory perception at a molecular level, Nobel laureates Richard Axel (Howard Hughes Medical Institute, New York, NY) and Linda Buck (Fred Hutchinson Cancer Research , Seattle, WA) cloned and characterized 18 different members of an extremely large multigene family that encodes seven transmembrane domain proteins whose expression is restricted to the olfactory epithelium (Ref.4). The members of this novel gene family encode a diverse family of OLFRs.

The OLFR gene family is one of the largest in the mammalian genome, comprising about 900 genes in human (~3% of the total genome) and 1,500 members in the mouse genome. In vertebrates, the OLFRs are located in the olfactory epithelium and in insects they are located on the antennae. Small subsets of OLFRs are also expressed in non-olfactory tissues, principally the testis, taste tissues, prostate, erythroid cells and notochord. Rather than binding to specific ligands like most receptors, OLFRs bind to structures on odor molecules. In mammals, odorants enter the nasal cavity, dissolve in the mucus that covers the luminal surface of the olfactory epithelium, and bind to specific OLFRs on the cilia of the dendrites of OSNs. Three cell types dominate the olfactory epithelium: the OSNs, the sustentacular or supporting cell, and the basal cell, which is a stem cell that generates olfactory neurons throughout life. OLFR neurons in the olfactory epithelium transduce molecular features of the odorants into electrical signals which then travel along the olfactory nerve into the olfactory bulb. The activation of different subsets of sensory neurons to different degrees is the basis for neural encoding and further processing of the odor information by higher centers in the olfactory pathway. Recent evidence by Buck and Axel has converged on a set of transduction mechanisms, involving G-protein-coupled second-messenger systems, and neural processing mechanisms, involving modules called glomeruli, that appear to be adapted for the requirements of different species. The G-Proteins initiate a cascade of intracellular signaling events leading to the generation of an action potential that is propagated along the olfactory sensory axon to the brain (Ref.1). The initial signaling is mediated by three distinct families of OLFR, each encoded by a multigene family. The OLFRs are extremely diverse in amino acid sequence, consistent with an ability to recognize a wide variety of structurally diverse odorants. In the olfactory epithelium, OLFRs couple to the GN-AlphaS, the GTP-bound form of G-Alpha-Olf (Olfactory G-protein), which stimulates ACIII (Type III Adenylyl Cyclase) and an increase in cAMP (cyclic Adenosine-3’, 5’-Monophosphate) that opens CNG (Olfactory Cyclic Nucleotide-gated) Channels causing membrane depolarization (Ref.2). A cAMP-signaling pathway is involved in mammalian chemosensory transduction in most OSNs. As intracellular cAMP levels increase, CNGs open to allow an influx of Na+ and Ca2+ into the cilia, leading to the generation of an action potential, which transduces signals to the olfactory bulb. The ligand sensitivity and selectivity is accomplished by the assembly of three different channel subunits, Alpha3, Alpha4, and Beta1b. Later, Ca2+ is pumped out of ORNs by Na+/Ca2+ exchangers, ClCn Channel and Ca2+-ATPases present in the cilia and dendritic knobs, thus maintaining Ca2+ homeostasis and returning the cell to electrical neutrality. Other modulators, such as calcium-binding protein Calm (Calmodulin) regulate changes in intracellular Ca2+ concentrations. The CNG channel protein harbors a binding site for the Ca2+/Calm complex. As soon as Ca2+/Calm bind to the CNG channels, the channels reduce their sensitivity to cAMP, and close again. Moreover, Ca2+/Calm activate an enzyme called PDE (Phosphodiesterase) that transforms cAMP to 5’AMP. Thus, although the odorant is still present, the excitation of the cell is strongly reduced.

Other second messengers, such as cGMP (cyclic Guanosine Monophosphate), are also produced by odorant stimulation. The decrease in cGMP concentration leads to closure of CNG channels, resulting in two effects, a decrease in Ca2+ influx and hyperpolarization of the membrane potential. The resulting decrease in intracellular Ca2+ concentration is important for adaptation. Lowered intracellular Ca2+ concentration disinhibits GCAP (Guanylate-Cyclase-Activating Protein), leading to activation of GC (Guanylate Cyclase) and resynthesis of cGMP. A second cGMP-regulated element that has been discovered in olfactory neurons is the cGMP-activated PDE2. PDE2 is expressed with GC in a subset of olfactory neurons. RGS (Regulators of G-protein Signaling) suppress GPCR (G-Protein Coupled Receptors) mediated signals by accelerating the hydrolysis of GTP bound to the G-Alpha subunit (Ref.3 & 5).

Olfactory information travels not only to the limbic system-primitive brain structures that govern emotions, behavior, and memory storage-but also to the brains cortex, or outer layer, where conscious thought occurs. In addition, it combines with taste information in the brain to create the sensation of flavor. Damage to the olfactory system can occur by traumatic brain injury, cancer, inhalation of toxic fumes, or neurodegenerative diseases such as Parkinsons disease and Alzheimers disease. These conditions can cause anosmia. Learning more about these links will help explain how odors affect our thoughts, emotions and behavior (Ref.4).