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CASE 45
A 15-year-old girl is brought to the pediatrician’s office because of concern
about her development. She has not gone through puberty as have other girls
her age. She reports never having had a period or breast development. She also
reports that she cannot smell things. She has difficulty recognizing pungent
odors such as trash and sweet fragrances such as perfume and flowers. On
physical examination, she is sexually infantile without development of axillary
or pubic hair or breast tissue and is unable to perceive odors. The remainder of
her examination is normal. She has a cervix and uterus on pelvic examination.
The patient subsequently is diagnosed with Kallmann syndrome.
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What type of axons constitute the olfactory nerves?
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Which kinds of chemicals does cranial nerve V detect?
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What nerve innervates the posterior third of the tongue, and what
tastes are detected there?
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CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 45: OLFACTORY/TASTE
SYSTEMS
Summary: A 15-year-old girl who is sexually infantile has anosmia consistent
with Kallmann syndrome.
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Types of fibers in the olfactory nerves: Unmyelinated C fibers (slow).
Chemicals detected by cranial nerve V: Noxious or toxic substances.
Innervation of the posterior third of tongue: Cranial nerve IX
(glossopharyngeal) detects sour and bitter tastes.
CLINICAL CORRELATION
Disorders of olfaction are caused by conditions that may interfere with the
olfactory epithelium, the receptors in the epithelium, or central neural pathways. Conditions that may interfere with the olfactory epithelium (transport
loss) include allergic, viral, and bacterial rhinitis; nasal polyps or tumors; nasal
septal deviation; and nasal surgery. Disorders of the receptors can be produced
by medications, infections, tumors, toxic chemical exposures, and a history of
radiation exposure. The list of central olfactory disorders is more extensive and
includes conditions caused by alcoholism, Alzheimer disease, medications,
diabetes, hypothyroidism, Kallmann syndrome, malnutrition, trauma,
Parkinson disease, vitamin deficiencies, and Huntington chorea. This patient
presents with Kallmann syndrome. Kallmann syndrome (hypogonadotropic
hypogonadism) is a disorder of both olfactory axonal and gonadotropin-releasing hormone (GnRH) neuronal migration from the olfactory placode in the
nose. This is why the patient is sexually infantile and has anosmia. The single
gene mutation is on the X chromosome and is responsible for functions necessary for neuronal migration.
APPROACH TO OLFACTORY AND TASTE
PHYSIOLOGY
Objectives
1.
2.
3.
4.
Describe sensory transduction in the olfactory system.
Understand the processing of olfactory information.
Describe sensory transduction in the gustatory system.
Know the central gustatory pathways.
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365
Definitions
Odorant binding proteins: Proteins secreted into nasal mucus that trap
and concentrate odorants, facilitating their interaction with odorant
receptor proteins.
Odorant receptor proteins: Members of a superfamily of G protein-coupled
receptors expressed in olfactory receptor neurons and encoded by about
1000 genes, with each protein binding a set of different odorants.
Umami taste: The fifth basic taste (in addition to salt, sour, sweet, bitter),
stimulated by the binding of glutamate and perhaps other amino acids to
ionotropic glutamate receptors expressed in some taste receptor cells.
DISCUSSION
Olfactory receptor cells are primary afferent neurons located in olfactory
epithelium within the upper levels of the nasal cavities. They are unusual
neurons because they are replaced continually throughout life, turning over
every 4 to 8 weeks. In addition to the olfactory receptor neurons, the olfactory
epithelium contains basal cells (stem cells to replace the receptor neurons) and
glial-like support cells. Each olfactory receptor neuron projects a thick dendrite tipped with cilia that end in the mucus layer. The mucus contains odorant-binding proteins that concentrate odorants, as well as enzymes and
antibodies. The antibodies provide important protection because olfactory
receptor neurons present a direct path into the brain that could be used by
viruses and bacteria present in aspirated air.
Each olfactory receptor neuron produces only one of a large family of about
1000 odorant receptor proteins that are localized to the cilia and display a high
specificity to particular odorant structures. Different odors stimulate different combinations of olfactory receptor neurons, and the average human
can recognize about 10,000 separate odors (with intensive training that
number may go up to about 300,000). Eighty percent of recognizable odors are
unpleasant, representing potentially toxic or dangerous substances.
Binding of an odorant to an odorant receptor causes excitation by the same
sequence of mechanisms in all olfactory receptor neurons. The odorant receptors are members of the enormous superfamily of G protein-coupled receptors, and binding of a specific odorant to a receptor activates the G protein
Golf, which in turn activates adenylyl cyclase. The resulting cyclic adenosine
monophosphate (cAMP) opens cAMP-gated cation channels, permitting the
influx of Na+ and Ca2+ (and the efflux of K+) and depolarizing the cell. The
Ca2+ (and additional Ca2+ that can enter through depolarization-activated
Ca2+channels) then activates Ca2+-activated Cl− channels. Because olfactory
receptor neurons have unusually high intracellular Cl− concentrations, opening
these channels causes an efflux of Cl− and further depolarization, initiating
action potentials. The action potentials are conducted relatively slowly along
very thin unmyelinated olfactory receptor neuron axons a short distance
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CASE FILES: PHYSIOLOGY
into the overlying olfactory bulb by the olfactory nerve (cranial nerve I).
Synapses from a very large number of olfactory receptor neuron axons are
made onto a much smaller number of relay neurons (mitral cells and tufted
cells) and inhibitory interneurons (periglomerular cells) within glomeruli in
the olfactory bulb. Information about different odorants is mapped on different glomeruli. The relay cells project directly to the olfactory cortex, which
then projects through the thalamus to the orbitofrontal cortex, where odor perception and discrimination occur, and to the amygdala and hypothalamus,
where emotional effects are produced.
The olfactory epithelium is also innervated by the trigeminal nerve
(cranial nerve V), which contains axons of nociceptive chemoreceptors that
have free nerve endings that detect noxious chemicals in the air, such as
ammonia and chlorine (as well as components of peppermint and menthol).
Activation of these epithelial nociceptors elicits defensive reflexes such as
sneezing, lacrimation, and respiratory inhibition. Humans also have a small
region of olfactory mucous membrane in the anterior nasal septum that may be
homologous to the vomeronasal organ in other mammals. Receptors in this
organ transduce olfactory stimuli by mechanisms different from those utilized
by other olfactory receptor neurons and project by different pathways to the
amygdala and hippocampus. In rodents, and possibly in humans, this accessory olfactory system detects pheromones that can influence sexual function.
Taste receptor cells are modified epithelial cells that are clustered in
taste buds on the tongue and, to a lesser extent, the palate, pharynx, epiglottis, and part of the upper esophagus. Each taste bud contains 50 to 100 receptor cells as well as basal cells for the generation of new receptor cells (which
live only about 10 days). Humans distinguish five tastes: salt, sour, sweet,
bitter, and umami, although human perception of taste usually involves contributions from olfaction and even texture and temperature. Unlike the olfactory and visual systems, which each utilize a single basic transduction
mechanism, transduction in taste receptor cells involves diverse mechanisms.
In salt taste receptors, transduction occurs when a rise in Na+ concentration
in the saliva results in sufficient influx of Na+ through voltage-insensitive
epithelial Na+ channels (ENaCs), which are always open, to depolarize the
cell. As in most taste cells, this leads to the opening of depolarization-activated
Ca2+ channels followed by Ca2+-dependent exocytosis of transmitter onto dendrites of primary afferent neurons. Sour taste transduction involves a similar
mechanism, with H+ ions permeating ENaCs to depolarize the cell. In addition, H+ ions can bind to and block K+ channels, which also depolarize the cell.
Sweet taste transduction occurs when sugars bind to specific G protein-coupled surface receptors that stimulate the synthesis of cAMP, ultimately closing
K+ channels.
Other G protein-coupled receptors bound by sugars stimulate the 1,4,5trisphosphate (IP3) pathway, which releases Ca2+ from intracellular stores,
directly enhancing Ca2+-dependent exocytosis of transmitter. Bitter taste
transduction involves binding of bitter compounds to receptors linked to a G
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367
protein, gustducin, which stimulates phosphodiesterase and decreases cAMP
and cyclic guanine monophosphate (cGMP) levels. In these cells cAMP and
cGMP lead to hyperpolarization, and so their degradation produces depolarization. In addition, other G protein-coupled receptors stimulate the IP3 pathway in bitter taste receptors, causing release of Ca2+ from intracellular stores
and enhanced transmitter release, as in some of the sweet taste receptors.
Finally, as in sour taste receptors, some bitter compounds can block K+ channels directly, depolarizing the cell. Umami taste receptors are stimulated by
certain amino acids, including L-glutamate, which binds to a metabotropic glutamate receptor that activates phosphodiesterase to decrease cAMP and cGMP
levels, as in some bitter taste receptor cells.
Primary afferent neurons activated by transmitter released from taste receptor cells project to the gustatory division of the solitary nucleus in the medulla
through the facial (cranial nerve VII), glossopharyngeal (cranial nerve IX), and
vagus (cranial nerve X) nerves. Information then is relayed through the thalamus to the primary gustatory cortex in the insular and orbitofronal regions.
Relatively little is known about central processing of taste.
COMPREHENSION QUESTIONS
[45.1]
Which of the following receptor cells is a primary afferent neuron?
A.
B.
C.
D.
E.
[45.2]
Auditory hair cell
Bitter taste cell
Olfactory receptor cell
Photoreceptor cell
Vestibular hair cell
Which of the following statements is true of odorant receptors in
olfactory receptor cells?
A. Most receptors respond to attractive rather than unpleasant odors.
B. Binding of an odorant stimulates the G protein, gustducin.
C. Odorant receptor proteins are expressed selectively near synaptic
active zones.
D. Odorant activation of a G protein–coupled receptor directly leads
to the opening of K+ channels.
E. Only one of a family of 10,000 receptor proteins is expressed in
each receptor neuron.
[45.3]
Release of transmitter from a salt receptor cell depends primarily on
Ca2+ accumulation resulting from responses to which of the following?
A.
B.
C.
D.
E.
Blockade of K+ channels by Na+
Gustducin activating the IP3 pathway
Influx of Na+ through voltage-insensitive epithelial Na+ channels
Opening of voltage-activated Na+ channels
Na+ binding to Ca2+ channels
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Answers
[45.1]
C. Olfactory receptor cells are true primary afferent neurons that conduct action potentials along their axons into the central nervous system
(CNS), where they synapse onto second-order neurons in glomeruli
within the olfactory bulb. The other receptor cells listed are epithelially
derived cells that lack axons. Sensory information from these cells is
conveyed by peripheral synapses to axonal terminals of primary afferent neurons that then project (often over long distances) into the CNS.
[45.2]
E. Each olfactory receptor neuron expresses only one of 10,000 possible receptor proteins. Odorant binding to its receptor acts through the G
protein Golf in peripheral receptor terminals, leading to the synthesis of
cAMP, which opens cAMP-gated cation channels that permit diffusion
of Na+, Ca2+, and K+, producing the net effect of depolarization and initiation of action potentials that travel to central synaptic terminals.
[45.3]
C. During a salty meal or drink, Na+ diffuses into salt taste receptor
cells through epithelial Na+ channels, leading to depolarization of the
cell, opening of voltage-gated Ca2+ channels, and Ca2+-dependent
exocytosis of neurotransmitter at synapses onto terminals of primary
afferent neurons in the taste buds.
CLINICAL CASES
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PHYSIOLOGY PEARLS
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Olfactory receptor cells have sensory cilia on an epithelial surface
and turn over every few weeks similar to epithelial receptor cells.
However, they are true neurons.
Odorants are concentrated and presented to olfactory receptor proteins by odorant-binding proteins in the mucus, which also contains antibodies and enzymes.
Each olfactory receptor neuron produces only one of a large family
of about 10,000 odorant receptor proteins.
Binding of an odorant to a receptor activates Golf, which increases
the synthesis of cAMP, which opens cAMP-gated cation channels, depolarizing the cell and promoting Ca2+ entry, which opens
Ca2+-activated Cl− channels, further depolarizing the cell so that
action potentials are initiated.
The major olfactory pathway goes from olfactory sensory neurons to
mitral and tufted cells in glomeruli in the olfactory bulb, then to
the olfactory cortex, and then to either the orbitofrontal cortex via
the thalamus or the amygdala and hypothalamus.
Defensive responses such as sneezing and lacrimation are triggered
by noxious chemicals that are detected by chemoreceptors in the
olfactory epithelium that send axons to the brainstem in the
trigeminal nerve.
Sensory transduction of the five basic tastes—salt, sour, sweet, bitter, and umami—involves many different mechanisms, sometimes for the same substance. In each case, the final step is an
increase in intracellular [Ca2+], which triggers Ca2+-dependent
exocytosis of transmitter from modified epithelial cells that have
become specialized for chemoreception.
REFERENCES
Connors BW. Sensory transduction. In Boron WF, Boulpaep EL, eds. Medical
Physiology. Philadelphia, PA: Saunders; 2003: 325-358.
Johnson DA. The chemical senses: smell and taste. In: Johnson LR. Essential
Medical Physiology. San Diego, CA: Elsevier Academic Press; 2003:849-859.
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