Smell information also goes to the thalamus, a structure that serves as a relay station for all of the sensory information coming into the brain. The thalamus transmits some of this smell information to the orbitofrontal cortex, where it can then be integrated with taste information. What we often attribute to the sense of taste is actually the result of this sensory integration.
This coupling of smell and taste explains why foods seem lackluster with a head cold. This happens because the thalamus sends smell information to the hippocampus and amygdala , key brain regions involved in learning and memory. Although scientists used to think that the human nose could identify about 10, different smells, Vosshall and her colleagues have recently shown that people can identify far more scents. Starting with different odor molecules, they made random mixtures of 10, 20, and 30 odor molecules, so many that the smell produced was unrecognizable to participants.
Predictably, the more overlap there was between two types of mixtures, the harder they were to tell apart. After calculating how many of the mixtures the majority of people could tell apart, the researchers were able to predict how people would fare if presented with every possible mixture that could be created from the different odor molecules. They used this data to estimate that the average person can detect at least one trillion different smells, a far cry from the previous estimate of 10, The one trillion is probably an underestimation of the true number of smells we can detect, said Vosshall, because there are far more than different types of odor molecules in the world.
No longer should humans be considered poor smellers. In fact, new research suggests that your nose can outperform your eyes and ears, which can discriminate between several million colors and about half a million tones. A beginner's guide to the brain and nervous system.
See how discoveries in the lab have improved human health. Taste, also called gustation , and smell, also called olfaction , are the most interconnected senses in that both involve molecules of the stimulus entering the body and bonding to receptors. Smell lets an animal sense the presence of food or other animals—whether potential mates, predators, or prey—or other chemicals in the environment that can impact their survival. Similarly, the sense of taste allows animals to discriminate between types of foods.
While the value of a sense of smell is obvious, what is the value of a sense of taste? Different tasting foods have different attributes, both helpful and harmful. For example, sweet-tasting substances tend to be highly caloric, which could be necessary for survival in lean times.
Bitterness is associated with toxicity, and sourness is associated with spoiled food. Salty foods are valuable in maintaining homeostasis by helping the body retain water and by providing ions necessary for cells to function.
Both taste and odor stimuli are molecules taken in from the environment. The primary tastes detected by humans are sweet, sour, bitter, salty and umami. The first four tastes need little explanation. The identification of umami as a fundamental taste occurred fairly recently—it was identified in by Japanese scientist Kikunae Ikeda while he worked with seaweed broth, but it was not widely accepted as a taste that could be physiologically distinguished until many years later.
The taste of umami, also known as savoriness, is attributable to the taste of the amino acid L-glutamate. In fact, monosodium glutamate, or MSG, is often used in cooking to enhance the savory taste of certain foods.
What is the adaptive value of being able to distinguish umami? Savory substances tend to be high in protein. All odors that we perceive are molecules in the air we breathe. If a substance does not release molecules into the air from its surface, it has no smell.
And if a human or other animal does not have a receptor that recognizes a specific molecule, then that molecule has no smell. Humans have about olfactory receptor subtypes that work in various combinations to allow us to sense about 10, different odors. Compare that to mice, for example, which have about 1, olfactory receptor types, and therefore probably sense more odors.
Both odors and tastes involve molecules that stimulate specific chemoreceptors. Although humans commonly distinguish taste as one sense and smell as another, they work together to create the perception of flavor. Odorants odor molecules enter the nose and dissolve in the olfactory epithelium, the mucosa at the back of the nasal cavity as illustrated in Figure The olfactory epithelium is a collection of specialized olfactory receptors in the back of the nasal cavity that spans an area about 5 cm 2 in humans.
Recall that sensory cells are neurons. An olfactory receptor , which is a dendrite of a specialized neuron, responds when it binds certain molecules inhaled from the environment by sending impulses directly to the olfactory bulb of the brain. Humans have about 12 million olfactory receptors, distributed among hundreds of different receptor types that respond to different odors.
Twelve million seems like a large number of receptors, but compare that to other animals: rabbits have about million, most dogs have about 1 billion, and bloodhounds—dogs selectively bred for their sense of smell—have about 4 billion. Interestingly, the response was quickly desensitized, with vessels returning to their constricted state after continued light exposure. Incubation with a G protein coupled receptor kinase 2 GRK2 inhibitor prevented this desensitization and amplified photorelaxation, suggesting G-protein-mediated phototransduction.
More recently, photorelaxation was also shown to involve Opn3 encephalopsin , as suppression of both Opn3 and Opn4 in mouse pulmonary artery almost completely abrogated blue wavelength — nm light-induced vascular relaxation Figure 2A. Figure 2. Effects of light exposure on pulmonary artery relaxation. B Representative traces show pulmonary arterial pressure P PA of isolated perfused rat lungs subject to hypoxia-induced pulmonary hypertension HPV. Reproduced with permission from Barreto Ortiz et al.
In the presence of GRK2 inhibitor, blue light both reverted and prevented phenylephrine-induced constriction of isolated pulmonary arteries. Furthermore, this treatment ablated single-cell constriction and reversed phenylephrine-induced depolarization of isolated pulmonary arterial smooth muscle cells.
More importantly, a phototherapeutic treatment consisting of GRK2 inhibition plus exposure to blue light induced significant vasorelaxation of pulmonary arteries from rats with chronic pulmonary hypertension PH , even when traditional vasodilatory drugs had only a modest effect.
Phototherapy also reduced pulmonary arterial pressure in the lungs of rats subject to acute hypoxia-induced PH Figures 2B,C , demonstrating the clinical potential of using phototherapy to treat vasoconstrictive diseases such as PH Barreto Ortiz et al. It is now well known that opsins perform numerous non-image-forming functions, with perhaps the most well studied being photoentrainment and circadian rhythm regulation.
In mammalian vertebrates, these functions are performed largely by opsins in the eye, as damage to the eyes ablates photoentrainment Nelson and Zucker, Photoentrainment is regulated both through light detection in rods and cones and through the effect of melanopsin in intrinsically photosensitive retinal ganglion cells ipRGCs Hannibal and Fahrenkrug, ; Panda et al.
More recently, neuropsin OPN5 was shown to be necessary for non-visual retinal photoentrainment in mammals, dictating molecular circadian rhythms ex vivo and revealing a role for what was until then an orphan photoreceptor Buhr et al. Despite the critical role of the eyes in mammalian photoentrainment, however, the CNS has been shown to play a crucial part in the photoreception that regulates circadian rhythm in a wide range of other animals.
In teleost fish and amphibians, for example, several photoreceptive sites have been identified outside the eyes, including the pineal complex, deep brain, and skin Peirson et al. In fact, the pineal complex has been the focus of several photoentrainment studies in non-mammalian vertebrates.
In a variety of species, the expression of several opsins has been confirmed, including pinopsin — nm , vertebrate ancient opsin — nm , exorhodopsin nm , parapinopsin and nm bi-stable , teleost multiple tissue opsin, and parietopsin nm Peirson et al. In zebrafish, the pineal gland contains an endogenous circadian pacemaker and expresses an opsin that is called exorhodopsin because of its similarity to rhodopsin Mano et al.
Other opsins have been found in zebrafish deep brain Kojima et al. This finding suggests that deep brain opsins also have functions outside of photoentrainment, particularly during development. Indeed, other studies have confirmed the role of opsins during zebrafish embryogenesis and identified vertebrate ancient long opsin in the CNS as a regulator of light-induced motor behavior and neural activity.
Drosophila have an alternative entrainment pathway that is mediated by cryptochrome Cry. Cry is a blue-light-sensitive protein that was found to aid in Drosophila photoentrainment and suggested to provide an independent cell-autonomous response to light in ventral lateral brain neurons Emery et al. Because silencing of Cry did not completely eliminate circadian photoentrainment, researchers suspected that another photoreceptor also played a role.
A recent study revealed a seventh rhodopsin in Drosophila Rh7 that contributes to photoentrainment by circadian pacemaker neurons in the brain, mediating a direct response to violet light nm Ni et al. These discoveries in a wide variety of animals suggest an adaptation to environmental light in the CNS that might have been lost during mammalian evolution, might still be present as a vestigial system, or might actually remain active in humans and have potential clinical applications.
Encephalopsin was the first opsin found outside of the ocular system in the mammalian brain Blackshaw and Snyder, Neuropsin also has been found in the human retina, brain, and testis Tarttelin Emma et al.
Melanopsin was also widely expressed at mRNA and protein levels in the human brain Nissil et al. Recent studies have shown that extraocular blue light delivered via the ear canals can influence human brain function and may have antidepressant effects Jurvelin et al. Furthermore, low-level light therapy, recently renamed photobiomodulation, has been suggested to provide neuroprotection against Parkinson's and other neurodegenerative diseases, and to provide beneficial effects in wound healing after traumatic events and in psychiatric disorders Schiffer et al.
The suggested mechanism of action entails increasing cytochrome oxidase and superoxide dismutase activities Rojas et al. Moreover, these studies prove that some light can penetrate the skull to produce physiologic responses in the human brain. The OPN3 gene has been implicated in asthma for specific populations.
It is expressed in the lung bronchial epithelia and in immune cells, suggesting that it may have a role in asthma susceptibility and immune response modulation White et al. How this response is modulated, however, has not been demonstrated. Interestingly, Yim et al. Perhaps more intriguing is the finding that opsins can serve a non-light-dependent sensing role. In it was discovered that Drosophila rhodopsin in fact mediates this response, as genetic silencing of the gene for this protein abolished the response, and introduction of mouse melanopsin restored normal thermotactic behavior Shen et al.
These findings oppose the dogma that opsin photoreceptors serve only to detect light and opens the possibility for unexplored physiologic functions. Mammalian sperm is extremely sensitive to temperature changes, and this study showed that opsins modulate temperature-induced movement of both mouse and human spermatozoa.
Interestingly, encephalopsin, melanopsin, rhodopsin, and neuropsin were each found to be distinctly localized within specific regions of the spermatozoa. In addition, ORs in the nose signal combinatorially; that is, rather than each scent being encoded by one neuron, a particular combination of neurons firing at the same time indicates a particular scent.
Because of this, the system has the capacity to identify a massive number of odors; although the precise number of odors that humans can discriminate remains unknown, it has been estimated to be as high as 1 trillion Bushdid et al. When an OR in an olfactory sensory neuron binds to its ligand, it activates an olfactory G-protein G olf , similar to G s , which subsequently activates adenylate cyclase 3 AC3 , leading to cAMP production.
The resultant influx of cAMP activates cyclic nucleotide-gated channels, ultimately leading to a series of ion fluxes that produce an action potential. It is worth noting that animals which are null for either G olf or AC3 cannot smell Belluscio et al.
Because mice at birth are dependent on smell to nurse, these anosmic mice typically die shortly after birth. Here, we will briefly highlight what is known about the roles of human, murine, or rat receptors in each of the systems listed below, as summarized in Table 1. To that end, in the text below we will refer to human ORs except when indicated otherwise; for murine and rat ORs, we will state whether or not a human ortholog is known.
The earliest report of ORs in the airway Gu et al. The study showed that exposure of the lung epithelium to volatile chemicals activates PNECs, leading to changes in the secretion of compounds that affect neighboring cells.
Intriguingly, the data also suggested that these processes may be altered in chronic obstructive pulmonary disease. In , Chang et al. Chang et al. That study demonstrated that ligands for OR51E2 modulated proliferation and cytoskeletal remodeling and that these effects were dependent on OR51E2 expression.
Intriguingly, these effects occurred in ASM from individuals both with and without asthma. Finally, a study in examined a non-small-cell lung cancer cell line Kalbe et al. Furthermore, helional acts on OR2J3 to induce apoptosis and inhibit cell proliferation, implying that this pathway may have therapeutic benefit.
A number of reports indicate that ORs play roles in a variety of cell types within the gastrointestinal system. To date, four reports have focused on enterochromaffin EC cells. The authors of that study found that ligands for these ORs altered both calcium signaling and serotonin release Braun et al.
Finally, a study from Kidd et al. Elsewhere in the gastrointestinal tract, researchers have investigated the role of OR51B4 in colorectal cancer. Weber et al.
Finally, the mouse OR Olfr, which does not have a known human ortholog, has been examined for a potential role in the gastrointestinal tract. In , one group showed that Olfr is expressed in alpha cells of mouse pancreatic islets, where it regulates glucagon secretion via calcium mobilization in response to its ligand, azelaic acid Kang et al. In , a second group showed that Olfr is expressed in liver and adipose tissue, where the authors proposed it contributes to a shift in fuel preference toward fats Wu et al.
The first functional example of an OR expressed outside of the nose was a report in showing that OR was expressed in human sperm. The authors suggested that the ligand for this OR bourgeonal may help direct the sperm in the direction of the egg to aid in fertilization Spehr et al. This landmark study was followed by a series of studies from the same group examining not only the role of OR Spehr et al. Finally, it has also been shown that ORs are expressed in the kidney and play functional roles in renal function.
A study in reported that several ORs, along with G olf and AC3, are expressed in the murine kidney, and that G olf and AC3 localize to the macula densa a chemosensory cell type Pluznick et al.
Subsequently, it was reported that Olfr78 the murine ortholog of OR51E2 localizes to juxtaglomerular cells in the kidney, where it acts to modulate renin secretion Pluznick et al. Olfr a murine OR without a clear human ortholog was reported to be expressed in renal proximal tubule cells, where it influences glucose handling.
Shepard et al. A number of other ORs and taste receptors have been identified in murine kidney Rajkumar et al. ORs have been found in blood cells, where they are associated with tauopathy Zhao et al. In addition, OR10J5 has been reported to play a role in angiogenesis it is expressed in human aorta and coronary artery, as well as an endothelial cell line Kim et al.
Another group reported that myocardial function is modulated via activation of an odorant receptor, OR51E1 Jovancevic et al. In , it was reported that exposure to odorants such as Sandalore induced ATP release from keratinocytes and thereby signaled to trigeminal neurons, implying that keratinocytes must have a way to sense the odorant Sondersorg et al.
These findings led to the hypothesis that OR2AT4 may play a role in wound healing. In , it was shown that a soluble ligand for MOR23 is secreted by muscle cells and that loss of MOR23 leads to increased myofiber branching Griffin et al. Subsequently, in , the same group published work in which a transgenic mouse for MOR23 was crossed with dystrophic mice.
They found that mechanical stress caused less damage to muscles from MORoverexpressing dystrophic mice than to those from control dystrophic mice Pichavant et al. OR51E2 has been reported to play a role in regulating cell growth of retinal pigment epithelial cells Jovancevic et al.
A landmark study in used next generation sequencing to profile the expression of ORs in 16 human tissues. The authors found that all tissues examined expressed at least one OR Flegel et al. In a similar vein, researchers in generated a novel antibody for Olfr murine OR with no clear human ortholog and found that it is expressed in a number of different cell types, including vascular endothelium, smooth muscle, and migrating neural crest Baker et al.
Thus, it is clear that ORs are expressed in additional cell types and tissues where their functions have yet to be uncovered. Sensory receptors are located in many different tissue types and their expression and function are altered during disease states.
Thus, they may represent new therapeutic targets for treating and altering disease progression. Many disease processes throughout the body have the potential to be treated with TAS2R agonists. TAS2R function in the upper airway has been well characterized. TAS2Rs in mucociliary epithelial cells of the upper airway and nasal tissue appear to be directly involved in sinus disease. Patients with chronic rhinosinusitis who have gene allelic frequencies favoring dysfunctional TAS2R38 are at higher risk for sinus surgery than those who are homozygous for functional TAS2R38 alleles Lee and Cohen, b ; Adappa et al.
Bitterness inhibits hunger. Activation of enteroendocrine cells via TAS2Rs results in increased ghrelin levels, acutely increasing food intake; however, it also leads to decreased gastric emptying, which, in mice, decreases food intake in the long term Janssen et al. In addition, bitter agonists administered to the stomach activate the nucleus tractus solitarii, and via vagal nerve activation, slow gastric emptying in human volunteers. Glendinning et al. Activation of TAS2Rs leads to smooth muscle relaxation in many different tissue types, providing therapeutic targets to treat diseases like pulmonary hypertension, reactive airway disease including asthma , and bladder spasms.
Studies showing vascular relaxation are limited to vessels in the brain and gastrointestinal tract; however, additional studies should be conducted to determine changes to peripheral and cardiac vasculature. Therefore their use presents high potential for side effects caused by unintended receptor activation.
Future research should focus on receptor-specific therapeutic medications to limit such effects. These receptors also contribute to progression of pathologic conditions, such as airway inflammation and asthma, and metabolic diseases of the pancreas, such as diabetes. The most significant role that TAS1Rs might have in the future is treatment for gastrointestinal diseases and obesity. In contrast to bitter receptor activation, sweet sensation promotes food intake.
Obesity decreases both bitter and sweet receptor expression in the duodenum and in areas of the murine brain involved in energy homeostasis. TAS1R3 is downregulated in the stomachs of obese patients Widmayer et al. These obesity effects suggest that TAS1R agonists may provide a therapeutic target to limit excess food intake. Like bitter taste receptors, TAS1Rs are also involved in bacterial recognition and immune cell function.
Stimulation of the innate immune response by altering sweet receptor expression may benefit those chronically infected or unresponsive to traditional anti-bacterial medications. These taste receptors may hold potential as therapeutic targets to treat these diseases, but this possibility requires investigation.
The discovery of nonvisual opsins in non-classic sensory organs prompts us to question whether these receptors can be engaged for therapeutic potential. The discovery that OPN4 receptors and TRPC channels in subcutaneous fat mediate a light-induced lipolytic activity suggests that blue-wavelength light might be used to reduce subcutaneous fat in a safe, noninvasive manner Ondrusova et al. Since subcutaneous white adipose tissue is the main fat deposit in the human body, this could have big implications to aid in fat deposit regulation and the associated metabolic disorders.
Some applications of photoreceptors are already being explored for skin health, such as the use of directed light therapy on the skin to treat acne Jung et al. Regarding these applications, OPN3 has been suggested to take part in melanogenesis, but no known photoreceptor has been associated yet with the acne reduction in response to blue or red light.
Furthermore, blue light exposure was shown to have a positive effect on hair growth, an effect mediated by OPN3. These results suggest that exposure to blue light may be a safe treatment for alopecia Buscone et al. The idea of using light to control the function of specific brain regions and to treat neurologic disorders has led to the field of optogenetics Deisseroth, Fiber-optic cables targeted to specific regions of the brain or other tissue can serve as the switch activators.
The limitations of this technology are 1 the need to transfect the light-activated switches using viral vectors and 2 the need for light-directing cables to be implanted in specific areas. With regard to the first limitation, the need for transfecting channels can be bypassed by recruiting the endogenously expressed OPNs in each tissue, or endogenous optogenetics.
The second limitation of using fiber optic cables can also be circumvented. Whereas blue light, the wavelength that activates the OPN3 and 4 receptors, has very limited tissue penetrance, NIR light has the potential for deep tissue penetration, including bone. Upconverting nanocrystals, nanoparticles coated in rare earth lanthanides, can convert 2 photons of NIR light to 1 photon of blue light Christ and Schaferling, The delivery of these crystals in tissues might therefore allow the use of NIR light to stimulate and activate endogenous OPN receptors by up-conversion to blue light Chen et al.
Given the expression of these OPN receptors in blood vessels and several brain tissues, this process may open up a potential light-based therapeutic path for the treatment of a wide variety of diseases. As discussed previously, the phototherapeutic approach of using directed blue light delivery along with GRK2 inhibition can effectively induce sustained vascular relaxation by activating OPN3 and OPN4, while preventing receptor desensitization by GRK2.
This treatment has been demonstrated to alleviate both chronic and acute PH in rat models, though its application could be extended to other cardiovascular diseases characterized by abnormal vasoconstriction Barreto Ortiz et al. Additionally, this phototherapy has the potential of inducing vasodilation in acute vascular obstruction events easily and safely, possibly buying precious time for a patient experiencing a cardiovascular episode such as a stroke or heart attack and allowing blood flow to the affected areas until surgical procedures to remove the obstruction can be performed.
Further research on the clinical applicability of phototherapy in vascular relaxation is therefore crucial. As ORs comprise the largest gene family in the genome, opportunities likely exist to leverage these receptors to modify physiologic and pathophysiologic processes. Such aspirations are currently limited by the fact that many ORs remain orphan receptors, with no known ligand. Because the most obvious strategy for commandeering these receptors for therapy would be to use agonists or antagonists, it is necessary that ligands be clearly identified for each of the ORs.
Although past efforts to identify ligands have been hampered by technical hurdles regarding OR trafficking in vitro , recent studies have made progress in this area Saito et al. ORs may lend themselves to being leveraged therapeutically in several potential areas, but we should caution that in all areas, future work is warranted to establish the feasibility and efficacy of potential interventions. OR51E2 has been shown to modulate proliferation and cytoskeletal remodeling in ASM from both asthmatics and non-asthmatics, implying that modulation of OR51E2 signaling may be beneficial in asthma Aisenberg et al.
A number of studies in several different systems have pointed to a potential role of ORs in controlling the growth of cancer cells.
Hence, modulating OR signaling might offer the possibility to inhibit cancer cell growth. However, the same OR has also been shown to stimulate cancer cell invasiveness Sanz et al. In addition, OR2J3 activation induced apoptosis and inhibited cell proliferation in a non-small-cell lung cancer cell line Kalbe et al. Olfr has been reported to play a role in the regulation of glucagon secretion Kang et al. In addition, Olfr modulates renal glucose handling by modulating Sglt1 Shepard et al.
Of note, Sglt1 is similar in function to Sglt2, a current drug target used to reduce blood glucose in type 2 diabetes. The suggestion that bourgeonal may act through an OR to help direct the sperm in the direction of the egg to aid in fertilization Spehr et al.
Olfr78 increases renin secretion by the kidney and also plays a role in modulating vascular tone Pluznick et al. Activation of OR51E1 has been associated with negative chronotropic and inotropic effects on the heart Jovancevic et al. Activation of OR2AT4 has been shown to promote cell proliferation and migration in keratinocytes Busse et al. When transgenic mice for MOR23 were crossed with dystrophic mice, mechanical stress caused less damage to the muscles from dystrophic mice with elevated MOR23 than to muscles from dystrophic mice with normal MOR23 levels Pichavant et al.
In conclusion, receptors traditionally believed only to identify and interpret light, sound, and taste also contribute to normal functions within many if not all other organ systems. Determining the function of sensory receptors in these organ systems and their roles under normal and pathophysiologic conditions has become a primary research focus with the potential to identify novel therapeutic targets to treat and possibly cure many medical diseases.
DB edited the final manuscript, contributing sections for novel therapeutic potential. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Adappa, N. T2R38 genotype is correlated with sinonasal quality of life in homozygous DeltaF cystic fibrosis patients. Forum Aller.
Adler, E. A novel family of mammalian taste receptors. Cell , — Aisenberg, W. Defining an olfactory receptor function in airway smooth muscle cells. An, S. Lung Cell. Ansoleaga, B. Neuroscience , — Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia. Avau, B. Targeting extra-oral bitter taste receptors modulates gastrointestinal motility with effects on satiation. Baker, N. Olfr, an orphan olfactory receptor, is expressed in multiple specific embryonic tissues.
These cookies do not store any personal information. Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website. Back to Parent Page. Share This Page. Smell The molecules that activate the sense of smell the technical name is olfaction are airborne; they enter the body via the nose and mouth and attach to receptor cells that line the mucus membranes far back in the nose.
Taste The other primary chemical sense, taste technically, the gustatory system , responds to molecules dissolved in liquid. Fact Sheets Neuroanatomy: The Basics. Fact Sheets The Senses: Vision All of our senses give us vital information about our surroundings, but the one we rely on most is vision.
Fact Sheets Connectivity The human brain is a network of networks: an intricate, integrated system that coordinates operations among billions of cells. Fact Sheets Cells of the Brain. Fact Sheets Stroke Although strokes are sudden, the brain injury they inflict typically evolves over the course of hours or even days. Fact Sheets Sex Hormones and the Brain Many of us think of hormones as chemical messengers that arrive during puberty to govern our reproductive development.
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