Download Notes0112

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Pre-Bötzinger complex wikipedia, lookup

Patch clamp wikipedia, lookup

Rheobase wikipedia, lookup

Threshold potential wikipedia, lookup

Membrane potential wikipedia, lookup

Alveolar macrophage wikipedia, lookup

Resting potential wikipedia, lookup

Electrophysiology wikipedia, lookup

Neuromuscular junction wikipedia, lookup

Cardiac action potential wikipedia, lookup

End-plate potential wikipedia, lookup

Clinical neurochemistry wikipedia, lookup

G protein-gated ion channel wikipedia, lookup

Stimulus (physiology) wikipedia, lookup

Signal transduction wikipedia, lookup

Transcript
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
Problem 1.12: Special Senses
Topic: Biochemical Aspects of Tasting
Prepared by: Joseph Mak
1) Overview
-
The elementary role of the gustatory system is to distinguish between food and
potential toxins, two components are required to accomplish this task:
(i)
-
-
-
A detection system of receptor cells capable of responding to the great
diversity of substances in the environment that might be ingested
(ii)
Neuronal pathways that refer taste information to appropriate cortical
structures
Pleasing sensations associated with food are necessary to maintain the appetite
and to initiate appropriate digestive and respiratory responses;
Unpleasing sensations associated with potential toxins elicit protective reflexes,
such as coughing, sneezing, gagging, or vomiting
Some taste responses are inborn, eg, a preference for sweetness and an aversion to
bitter tastes.
However, the gustatory system is highly modifiable by experience. Illness that
occurs soon after ingestion of a particular food can greatly diminish subsequent
preferences for that food
Taste can be acquired so that some bitter tastes, like quinine, are tolerated or even
enjoyed.
Taste receptors are classified as modified epithelial cells rather than true neurons.
They occur in clustered structures called taste buds, each of which contains 50 to
100 receptor cells arranged like slices of an orange with a central opening or pore
open to the surface of the tongue.
The taste bud also contains basal cells that are the stem cells for the production of
new taste receptors
The typical life span of taste receptors is 1 to 2 weeks. Taste receptors synapse on
dendrites of afferent gustatory fibres projecting into the taste bud.
2) The Five Basic Tastes
-
-
-
Humans perceive five basic tastes: salt, sour, sweet, bitter and umami.
Further distinctions are made based on combinations of these basic sensations, and
subtleties can be made by combinations of smell and taste, and to a lesser extent
the temperature and texture of food
The five basic tastes are derived from different transduction mechanisms located
on taste receptor cells and their specific interactions with different types of
molecules
In general,
(i)
Acids elicit a sour taste
(ii)
Salt elicits a salty taste
(iii)
Sugars, some proteins, and amino acid artificial sweeteners such as
saccharin and aspartame invoke sweetness
Page 1
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
(iv)
(v)
-
Ions such as potassium and magnesium and organic compounds such as
quinine and coffee taste bitter
Umami, recently recognized as an additional basic taste, is associated with
some amino acids such as glutamate, the common culinary form of which
is monosodium glutamate, commonly known as MSG. These compounds
interact with taste receptors and cause an increased release of transmitter,
which in turn stimulates primary afferent taste fibres.
There are four mechanisms by which chemicals cause increased transmitter
release from taste receptors
(i)
(ii)
(iii)
(iv)
direct passage of ions through ion channels
blockage of ionic channels
opening of ionic channels
activation of second-messenger systems through ligand interactions with
membrane receptors
2.1 Salt
-
-
-
Sodium ions are largely responsible for establishing a salty taste
Sodium ions diffuse through the pore of the taste bud and enter the taste receptor
cell through sodium-selective channels present in the cell membrane.
These channels are characterized by their sensitivity to the drug amiloride and
their insensitivity to changes in voltage. Thus they are different from sodium
channels involved in propagation of action potentials
The entry of positively charged ions depolarizes the taste receptor cell, opens
voltage-dependent calcium channels, and increases the influx of calcium, thereby
allowing calcium to enter the cell and cause the release of neurotransmitter
Hydrogen ions can also enter these channels, therefore acidic food has a salty taste
2.2 Sour
-
-
A sour taste is associated with acidic substances that affect sour-sensitive taste
receptors in two ways.
(i)
Acids in solution generate hydrogen ions that can permeate the amiloridesensitive sodium channel described and cause depolarization-stimulated
release of neurotransmitter in the same manner as sodium ions.
(ii)
Hydrogen ions also block a potassium-selective channel within the
membrane.
This also causes depolarization because the normal movement of
potassium out of the cell is blocked, and more positively charged
potassium ions are trapped intracellulary
(Since intracellular content of K+ is high and is continually lost from the
cell, as these potassium channels are blocked, K+ then accumulates inside
the cell, and hence causes depolarization)
Foods that cause depolarization and increased transmitter release through both of
these mechanisms are perceived as sour
Page 2
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
-
Those that cause depolarization only through diffusion of cations through the
sodium channel are perceived as salty
2.3) Sweet
-
-
There are specific membrane receptor proteins on some taste cells that bind sugars
and other sweet-tasting substances.
Binding to these receptor sites activates a second messenger system similar to the
one associated with noradrenergic receptors. When the receptor protein is
activated it activates a Gs-protein, which stimulates adenylyl cyclase to produce
cAMP. This cAMP releases protein kinase A (PKA) from its regulator proteins,
and PKA phosphorylates potassium channels, closing them and depolarizing the
cell. (Details of which is dealt with in later sections)
As a result, sweet-sensitive taste cells are depolarized
2.4) Bitter
-
-
Some bitter compounds (eg, calcium ions and quinine) decrease conductance of
potassium-selective channels similar to the mechanisms used for detection of
sweetness
Other bitter substances bind to specific membrane receptors that activate
secondary-messenger systems and cause membrane depolarization
One type of bitterness receptor triggers an increased production of the intracellular
messenger, inositol triphosphate (IP3)
In all other transduction mechanisms described earlier, depolarization of the
receptor cell causes an increase in calcium influx through votage-sensitive
calcium channels, and calcium ions act as the trigger for release of
neurotransmitter.
This is not so in the case of the IP3 transduction mechanism
Here, the membrane potential is not altered; rather, IP3 causes the release of
calcium from internal storage sites, which in turn directly stimulates
neurotransmitter release.
2.4) Umami
-
This is a taste sensation associated with certain amino acids such as glutamate and
perhaps arginine
These amino acids bind to and activate a cation-permeable channel, causing
depolarization in a similar manner to glutamate activation of cation channels in
the brain
Page 3
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
Fig 1.12-1 Transduction mechanisms for salt, sour, umami, sweet and bitter
All taste receptors release neurotransmitters in response to an increase in free
intracellular calcium, usually as a result of depolarization that opens reactive
calcium channels. This cause of this depolarization varies with the specific
receptor cell.
(A) Salty taste is tranduced by amiloride-sensitive sodium channels that are
always open. When the sodium concentration increases on the surface of the
microvilli, it can enter the channels and depolarize the cell. Hydrogen ions
can also enter these channels, and therefore acidic food has a salty taste.
Page 4
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
(B) Sour taste is elicited when hydrogen ions act directly on open potassium
channels, closing them and depolarizing the cell.
(C ) Glutamate (eg, in MSG) binds to the receptor that opoens, allowing all
small cations to pass, including sodium, potassium, and calcium. The net effect
of these ionic movements is to depolarize the cell
(D) Sweet tastes, such as sugars and certain proteins, produce depolarization by
a chain of events that resemble many CNS neurotransduction systems. (dealt
with in later sections)
(E) There at least two types of bitter receptors. Quinine stimulates the bitter 1
receptor and closes potassium channels.
(F) Other bitter substances bind with a bitter 2 receptor, which activates a Gprotein, which in turn causes the production of inositol triphosphate (IP3). IP3
triggers the release of calcium from internal stores, stimulating neurotransmitter
release without an intervening depolarization.
3) Central Gustatory Pathways
-
-
-
-
-
Taste receptors synapse with dendritic elements of the primary afferent neurons of
the gustratory pathway, causing the neurons to fire in response to appropriate
stimuli above threshold levels
These afferent fibres arise from cell bodies within three cranial nerve ganglia
Afferent fibres within the facial nerve (cranial nerve VII) arise from the
geniculate ganglia and innervate the anterior two-thirds of the tongue.
Fibres from glossopharyngeal nerve (cranial nerve IX) arise from the inferior
glossopharyngeal ganglia and innervate the posterior one third of the tongue
Fibres from the vagus nerve (cranial nerve X) arise from the inferior vagal
ganglia and innervate the smattering of taste buds found in throat regions,
including the glottis, epiglottis and pharynx.
Central projections from these three cranial nerve ganglia enter the brain stem
along the lateral aspect of the medulla and converge to make synaptic contact with
cells in the rostral or gustratory division of the solitary nucleus of the medulla.
Ascending fibres from the solitary nucleus make a synaptic connection in the
ventral posterior medial nucleus of the thalamus.
Thalamic neurons then project to the primary gustratory cortex in the insular and
orbitofrontal regions.
The large number of distinguishable tastes is represented by population responses
of various central taste neurons rather than by activation of individual tastespecific neurons
~ Coding for the four primary taste qualities is not based on complete selectivity
of the chemoreceptors for the different qualities.
~ Instead, a given chemoreceptor responds to stimuli that evoke several different
taste qualities, although perhaps most vigorously to one.
Page 5
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
~ Recognition of taste quality appears to depend on the patterned input from a
population of chemoreceptors. The intensity of the stimulus is reflected in the total
amount of evoked activity
Fig 1.12-2 Central
Gustratory Pathway
Central projections of
taste buds. Information
from taste buds enters the
ventral surface of the
medulla via three pairs of
cranial neurons and
synapses in the rostral or
gustatory division of the
solitary nucleus.
Secondary neurons
carrying gustatory
information project to the
ventral posterior medial
nucleus of the thalamus,
where it is relayed to the
cerebral cortex for
conscious and
appreciation.
Here shows oral cavity
and dorsal view of the
brain stem showing the
three cranial nerves that
carry information is
processed ipsilaterally.
4) Cellular Communication
The above transduction mechanisms described are some means of cellular
communication, this section deals with the basic mechanisms of them. This section is
for better understanding of the biochemical sensation of taste.
-
-
Cells respond to a variety of external stimuli and transduce these signals into
electrical and biochemical changes. In many instances this involves the interaction
of a signal with a receptor in the plasma membrane. This may lead directly to
activation of ion channels, but more commonly it induces the production of
intracellular messengers that then regulate cell function
Important intracellular pathways include the cyclic adenosine monophosphate
(cAMP) system, polyphosphoinositide system
Page 6
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
-
For chemical stimuli (eg, gustatory, olfactory, neurotransmitters, hormones,
growth factors, etc) the first event leading to a cellular response is the interaction
of the chemical signal (ligand) with its receptor.
Receptors
- Receptors are molecular entities, either proteins or glycoproteins, that bind ligands
with high affinity
Ligands
- an organic molecule that donates the necessary eletrons to form coordinate
covalent bonds with metallic ions, as oxygen is bound to the central atom of Hb.
This term is also used to indicate any ion or molecule that reacts to form a
complex with another molecule, frequently a macromolecule.
Ion channels
- Ion channels are membrane proteins that contain small, highly selective aqueous
pores. They allow specific ions, eg, Na+, K+, Ca2+ or Cl- to move down their
electrochemical gradients across the membrane, and are often named after the ions
for which they show the greatest selectivity.
- The major types of regulated ion channel include:
(i)
voltage-gated channels, in which the sensor responds to the voltage
across the membrane, eg, the voltage-sensitive Na+ channel involved in
action potential generation
(ii)
chemically gated channels, in which the sensor is sensitive to a chemical
signal such as the binding of a ligand to a receptor that forms part of the
channel, eg, the acetylcholine receptor channel involved in neuromuscular
transmission; and
(iii)
mechanically gated channels, in which the sensor is sensitive to
mechanical deformation of the membrane, eg, stretch-activated channels
on sensory nerve terminals.
4.1 Intracellular messengers
-
The first such intracellular chemical to be indentified was cyclic adenosine
monophosphate (cAMP), named a second messenger
It is now known that many chemical stimuli result in an increase in concentration
of cAMP in their target cells.
Ca2+ is also an important intracellular messenger; stimuli may open channels
allowing it to flow into the cell or be released from intracellular stores in
endoplasmic reticulum. Other important intracellular messengers (e.g, cyclic
GMP, IP3 and diacylglycerol) have since been identified.
4.1.1 G proteins
-
In both the cAMP and the polyphosphoinostide systems that are described in
detail later in this section, the step that follows the binding of the ligand to its
Page 7
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
-
-
receptor at the membrane surface, and that initiates the cell response, is the
activation of a regulatory protein that binds GTP (Guanosine triphosphate) Hence
this protein is called a G protein.
About 100 different ligand-receptor complexes are now known to activate G
proteins, which have come to be known as universal transducers
G proteins consist of  subunits. In the inactive state, the  group of the G
protein binds guanosine diphosphate (GDP), and the protein can be represented as
“-GDP”. (See Fig 1.12-3)
Following occupation of a surface receptor, a conformational change in the G
protein results in the exchange of GDP for cytoplasmic GTP, giving -GTP.
The -GTP subunit then dissociates from the -subunits and binds to an effector
molecule (e.g, an enzyme such as adenylate-cyclase, or a channel protein)
The -subunit has GTPase activity, it converts GTP back to GDP and is
recombined with -subunits and the inactivated G protein is reconstituted.
Fig 1.12-3
Role of the G protein in
transduction.
The ligand binds to the receptor
in the plasma membrane and
activates the G protein, which
consists of - subunits. This
allows the -subunit to exchange
its bound GDP for GTP. The GTP then dissociates from the subunits and stimulates an
effector (e.g, Adenylate cyclase,
ion channel, etc) The GTPase on
the -subunit breaks down GTP
to GDP, causing the -GDP to
dissociate from the effector and
recombine with the -subunits.
Page 8
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
4.1.2 cAMP system
-
-
-
Adenylate cyclase (an enzyme) catalyses the synthesis of cAMP from adenosine
triphosphate (ATP)
Fig 1.12-4 summarizes the events that follow increased cAMP production. The
raised level of cAMP within the cell stimulates protein kinase A, this may lead to
specific changes in ion channel gating, enzyme activity, protein synthesis or gene
activation, depending on the tissue involved.
Eventually, the concentration of cAMP is restored to its basal level by degradation
to AMP, this step being catalysed by the enzyme cyclic nucleotide
phosphodiestease
Importance of many hormone and neurotransmittors are mediated by cAMP:
(i)
Only certain tissues contain receptors which will react with a particular
ligand to produce an increase in intracellular cAMP.
(ii)
The responses of various tissues to raised levels of cAMP are different.
For example, in response to an increase in cAMP, liver cells break down
glycogen but heart cells increase their rate and strength of contraction.
Fig 1.12-4 Signals acting through cAMP. The ligand binds to its receptor (R) on
the outer surface of the plasma membrane. At the inner surface are the GTPregulatory protein (G) and the enzyme adenylase cyclase (AC), which catalyses
the conversion of ATP to cAMP. Binding of the ligand to the R-G complex
allows the G unit to bind GTP and stimulate adenylate cyclase activity. cAMP
activates protein kinase A, which phosphorylates cellular proteins to produce the
characteristic cellular response.
4.1.3 Polyphosphoinositide system
-
Phosphoinositides are a family of plasma membrane phospholipids containing
inositol.
Binding of a hormone to its receptor activates a different G protein
This in turn stimulates a phosphodiesterase (phospholipase C) in the plasma
membrane, which cleaves PIP2 (phophatidylinositol 4,5-bisphophate) in the
membrane to form IP3 (inositol trisphosphate) and DAG (diacylglycerol)
Page 9
Problem 1.12: Special Senses
Topic: Biochemical Aspect of Tasting
-
IP3 migrates to the endoplasmic reticulum where it stimulates the release of Ca2+
DAG remains in the membrane and, in the presence of Ca2+, activates protein
kinase C. This enzyme phosphorylates many intracellular proteins, including some
that are also phosphorylated by protein kinase A.
Fig 1.12-5 Signals operating through the polyphosphoinositide system.
The binding of the ligand to its receptor (R ) in the plasma membrane activates
the enzyme phospholipase C (PLC) via the G protein. This enzyme cleaves PIP2
to IP3 and DAG. IP3 mobilizes Ca2+ from the endoplasmic reticulum while
DAG, in the presence of Ca2+, activates the enzyme protein kinase C (PKC), and
these actions lead to specific cellular responses. IP3 and DAG are rapidly
metabolized and their end-products recycled to form PI, which is phosphylated
to form PIP and finally PIP2.
References: 1) Lecture Notes on Human Physiology 3rd Ed
612 L47
2) Esssential Medical Physiology 2nd Ed by Leonard R. Johnson
D 612 E78 J
Page 10