c 2 biofiz sistem sensz 2011-2012

8/13/2019 C 2 Biofiz Sistem Sensz 2011-2012

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LIGAND-RECEPTOR

INTERACTION

Biophysics of CHEMICAL

SENSES: taste and smell


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BACKGROUND CONCEPTS

Overview of the smell and taste systems

Odor and food molecules activate membranereceptors

The complicated processes of smelling and tasting beginwhen molecules detach from substances and float into

noses or are put into mouths. In both cases, the moleculesmust dissolve in watery mucous in order tobind(ligand-receptor interaction) and to stimulate specializedsensory cells

These cells transmit messages (electric impulses orneural signals) to brain centers where the interpretationtake place and behavioral response is generated: weperceive odors or tastes, and where we remember people,

places, or events associated with these olfactory (smell) andustator (taste) sensations.


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A membrane receptor will respond to severalstructurally related molecules

The activation of receptors by discrete chemical structuresis not absolute, because a given membrane receptor willaccept a number of structurally similar ligands.

Nevertheless, we can discriminate many thousands ofsmells and tastes, even though some chemicals stimulatethe same receptor.

How are we able to distinguish these?

Our ability results from the fact that most substances weencounter are complex mixtures, which activate differentcombinations of odor and taste receptors simultaneously.

Thus, each substance we smell or taste has a unique

chemical signature.


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In the laboratory, researchers frequently test people oranimals with pure individual chemicals in order to findthe best stimulus for a receptor, but in the real worldwe seldom encounter these molecules alone.

Although we do have overlap in the response of tasteand smell receptors to ligands, scientists haveidentified quite a number of receptor types.

Humans probably have hundreds of kinds of odormembrane receptors, and on the order of 50 to 100different kinds of taste receptors.

It is true that we typically describe only five categoriesof tastes (see below): this means that each of the

categories probably has more than one type ofreceptor. Further research will show how this puzzle fits

together.


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The neural systems for taste and smell shareseveral characteristics

Although the neural systems (sensory cells, nerve

pathways, and primary brain centers) for taste and smellare distinct from one another, the sensations of flavorsand aromas often work together, especially duringeating. Much of what we normally describe as flavor

comes from food molecules wafting up our noses.Furthermore, these two senses both have connections tobrain centers that control emotions, regulate food andwater intake, and form certain types of memories.

Another similarity between these systems is the constantturnover of olfactory and gustatory receptor cells. Afterten or so days, taste sensory cells die and are replaced byprogeny of stem cells in the taste bud.


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Although an individualtaste bud cannot be seenwithout a microscope

(Figure 1, right), it lookssomething like a balloonwith a small opening atthe tongue surface: this isthe taste pore. Into thepore come food and drinkmolecules, fitting intomembrane receptorslocated on small finger-

like protrusions calledmicrovilli at the tops oftaste sensory cells. Themicrovilli increase the

surface area of the cell(see Figure 2).

Figure 1 - taste bud


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Figure 2. A tastesensory cell and the fivetypes of taste receptors.

Flavor molecules fitinto receptors on themicrovilli at the top ofthe cell, causingelectrical changes thatrelease transmitter

onto the nerve endingat the bottom of thecell. The nerve carriestaste messages to the

brain. See text fordetails on receptortypes. Figure courtesyof Dr. Tim Jacob,Cardiff University,

Wales


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How do these cells begin the process that leads to recognizingtastes? As mentioned in Section 1, the membrane receptors on

sensory cells contain molecular pockets that accommodateonly compounds with certain chemical structures.According to current research, humans can detect five basictaste qualities: salt, sour, sweet, bitter, and peppered.Investigations of the molecular workings of the first four showthat salt and sour receptors are types of ion channels, whichallow certain ions to enter the cell, a process that resultsdirectly in the generation of an electrical signal.

Sweet and bitter receptors are not themselves ion channels,but instead, like olfactory receptors, accommodate parts ofcomplex molecules in their molecular pockets.)


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When a food or drink molecule binds to a sweet or a bitterreceptor, an intracellular "second messenger" system

(usually using cyclic AMP) is engaged. After several steps, concluding with the opening of an ion

channel, the membrane of the taste receptor cell producesan electrical signal. (The second messenger system is a

signaling mechanism used in many sensory nerve cells aswell as in other cells in the body).

Although humans can distinguish only five taste qualities,more than one receptor probably exists for some of these.

This is supported by the finding that some people cannotdetect certain bitter substances but do respond to others,indicating that only one kind or class of bitter receptor is

missing, probably as the result of a small genetic change.


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Although humans can distinguish only five tastequalities, more than one receptor probably exists forsome of these. This is supported by the finding thatsome people cannot detect certain bitter substances

but do respond to others, indicating that only onekind or class of bitter receptor is missing, probably asthe result of a small genetic change. (You can

demonstrate this with phenylthiourea-impregnatedpapers in the classroom, as described in the TeacherGuide.)


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Taste signals go to the limbic system and to the cerebralcortex

Where do taste messages go once they activate thereceptor cells in the taste bud? The electrical message

from a taste receptor goes directly to the terminal of aprimary taste sensory neuron (Figure 2), which is incontact with the receptor cell right in the taste bud. Thecell bodies of these neurons are in the brainstem (lower

part of the brain, below the cerebrum and their axonsform pathways in several cranial nerves.


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Once these nerve cells get electrical messages fromthe taste cells, they in turn pass the messages onthrough relay neurons to two major centers: thelimbic system and the cerebral cortex as shown in

Figure 3. The limbic system (which includes the

hippocampus, hypothalamus and amygdala) isimportant in emotional states and in memory

formation, so when taste messages arrive here, weexperience pleasant, or aversive, or perhapsnostalgic feelings.


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Figure 3. Central taste pathways. (See text for explanation)


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In the frontal cerebral cortex, conscious identificationof messages and other related thought processes takeplace.

The messages from the limbic system and the frontalcortex may be at odds with each other.

For example, if you are eating dinner at a friend's

home and the first bite of a food item is bitter, you mayfeel an aversion to eating more.

But if you know the food is merely from anotherculture and not harmful, you may make a conscious

decision to continue eating and not offend your hosts. Thus, taste messages go to more primitive brain

centers where they influence emotions and memories,and to "higher" centers where they influence conscious

thought.


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Ligand receptor interaction

In biochemistry and pharmacology, a ligand (from the

Latin ligandum, binding) is a substance that forms acomplex with a biomolecule to serve a biological purpose.In a narrower sense, it is a signal triggering molecule,binding to a site on a target protein.

The binding occurs by intermolecular forces, such as ionicbonds, hydrogen bonds and van der Waals forces. Thedocking (association) is usually reversible (dissociation).Actual irreversible covalent binding between a ligand and

its target molecule is rare in biological systems. In contrastto the meaning in metalorganic and inorganic chemistry, itis irrelevant whether the ligand actually binds at a metalsite, as is the case in hemoglobin.


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Ligand binding to a receptor alters the chemicalconformation, which is the three dimensional shape ofthe receptor protein.

The conformational state of a receptor protein

determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and

neurotransmitters.

The tendency or strength of binding is called affinity.

Radioligands are radioisotope labeled compounds andused in vivo as tracers in PET studies and for in vitrobinding studies.

R /li d bi di ffi i


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Receptor/ligand binding affinity

The interaction of most ligands with their binding sites

can be characterized in terms of a binding affinity. Ingeneral, high affinity ligand binding results fromgreater intermolecular force between the ligand and itsreceptor while low affinity ligand binding involves less

intermolecular force between the ligand and itsreceptor. In general, high affinity binding involves alonger residence time for the ligand at its receptorbinding site than is the case for low affinity binding.

High affinity binding of ligands to receptors is oftenphysiologically important when some of the bindingenergy can be used to cause a conformational changein the receptor, resulting in altered behavior of an

associated ion channel or enzyme.


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A ligand that can bind to a receptor, alter the functionof the receptor and trigger a physiological response iscalled an agonist for that receptor. Agonist binding to a

receptor can be characterized both in terms of howmuch physiological response can be triggered and interms of the concentration of the agonist that isrequired to produce the physiological response.

High-affinity ligand binding implies that a relativelylow concentration of a ligand is adequate to maximallyoccupy a ligand-binding site and trigger a physiologicalresponse. Low-affinity binding implies that a relatively

high concentration of a ligand is required before thebinding site is maximally occupied and the maximumphysiological response to the ligand is achieved. In theexample shown to the right, two different ligands bind

to the same receptor binding site.


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Only one of the agonists shown can maximallystimulate the receptor and, thus, can be defined as a"full agonist".

An agonist that can only partially activate thephysiological response is called a "partial agonist".Ligands that bind to a receptor but fail to activate thephysiological response are receptor "antagonists".

In this example, the concentration at which the fullagonist (red curve) can half-maximally activate thereceptor is about 5 x 109 Molar (nM = nanomolar).


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An agonist is a chemical that binds to areceptor of a cell and triggers a response bythat cell.

Agonists often mimic the action of a naturallyoccurring substance.

Whereas an agonist causes an action, anantagonist blocks the action of the agonist

and an inverse agonist causes an actionopposite to that of the agonist.


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In the example shown to the left, ligand-binding curvesare shown for two ligands with different bindingaffinities.

Ligand binding is often characterized in terms of theconcentration of ligand at which half of the receptorbinding sites are occupied, known as the dissociationconstant (Kd).

The ligand illustrated by the red curve has a higher

binding affinity and smaller Kdthan the ligand illustratedby the green curve.

If these two ligands were present at the same time, moreof the higher-affinity ligand would be bound to the

available receptor binding sites. This is how carbon monoxide can compete with

oxygen in binding to hemoglobin, resulting incarbon monoxide poisoning.


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c 2 biofiz sistem sensz 2011-2012

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