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Robertson-1
Dear Super-)O\+HDOWK6FL¶V
Congratulations on your acceptance to the BHSc (Honours) Program at McMaster University! We are
delighted that you will be joining us for the 2013-2014 year! One of the courses you will be taking is Cellular and
Molecular Biology (HSC 1I06). You will receive an official course outline that will present its basic structure, and
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course in the first term.
The main focus of this course is cellular communication, although the points at which it can be controlled
are also very important. Every week you will attend one lecture that focuses on intracellular events leading to the
production of signalling molecules, and another lecture that solely addresses signalling molecules and their
functions. You will eventually see how these concepts converge. When learning about intracellular processes, you
will cover fundamental concepts about the route from DNA to RNA and finally to proteins.
Deoxyribonucleic acid (DNA) is a double-stranded helix structure that stores genetic information. It is built
from nucleotides composed of a deoxyribose sugar, a phosphate group, and one of the four nitrogenous bases adenine (A), thymine (T), cytosine (C), or guanine (G). DNA replication is a semi-conservative process that
involves each strand of the double helix acting as a template for the creation of a complementary strand with the
help of enzymes. We can control which genes are expressed in DNA through direct interaction, mutations, or
³NQRFNLQJRXW´FHUWDLQJHQHs from the strand using nucleases. The function of a gene can be understood by
observing what occurs when the gene is not properly expressed.
After replication, DNA is converted to RNA through a process known as transcription. During transcription
the helix of DNA is unzipped, allowing the RNA polymerase enzyme to construct a single strand of RNA from the
DNA template, using the base uracil (U) instead of thymine. Since transcription is an integral step of gene
expression, the production of the final protein can also be controlled at this stage. Manipulating protein expression
is the simplest at this step, because there are many control points that are better understood, and easier to target.
For example, transcription can be controlled with gene regulatory proteins (GRPs), which bind to specific
sites on DNA to either activate or inhibit transcription. Along with GRPs, you can also use small interfering RNA
(siRNA) to alter gene expression. siRNA is double-stranded RNA that normally excises introns, but can also be
used to degrade mRNA.
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initiated when two ribosomal subunits attach to the mRNA at the start codon (a base triplet) along with a tRNA
carrying an amino acid (the functional unit of a polypeptide). Multiple tRNA units continue binding, bringing
amino acids with them that are linked together with peptide bonds to create the polypeptide. This process ends
when the stop codon is recognized and a releasing factor frees the peptide chain.
Finally, once a protein has been formed, the endoplasmic reticulum ensures that the protein is folded
properly. It is then packaged and sent to the Golgi, where it is stored until it leaves the cell via exocytosis. If a
protein is misfolded in the cytosol, FKDSHURQHSURWHLQVPD\IL[LWWKURXJKDSURFHVVNQRZQDVWKH³KHDW-shock
UHVSRQVH´,IWKHPLVIROGHGSURWHLQLVLQWKHHQGRSODVPLFUHWLFXOXPFKDSHURQHSURWHLQVDORQJZLWKRWKHUHQ]\PHV
ZLOOGHJUDGHLWWKURXJKWKH³XQIROGHGSURWHLQUHVSRQVH´%\GHWHFWLQJ the presence of proteins using different
analytical techniques, scientists can conclude whether or not a certain gene is being expressed.
As the final product of gene expression, proteins serve as structural units, enzymes, antibodies, receptors, or
signalling molecules. Signalling molecules have many important functions in the body, allowing for cell
communication by acting as messenger molecules. All signalling molecules, when synthesized, may be stored and
upon release, elicit a response. Each molecule will eventually have its effects terminated. Each point in the pathway
may be controlled through specific mechanisms.
This pathway begins when the molecule is produced. Neurotransmitters, a type of signalling molecule, are
either small molecule neurotransmitters or neuropeptides. Small molecules are synthesized in the axon terminals of
a nerve, whereas neuropeptides are synthesized in the cell body. Production of signalling molecules can be
attenuated by inhibiting synthetic enzymes. Additionally, if a signal molecule is a protein, it can be controlled at the
genetic level. Though not all molecules are stored before release, those that are can be stored in granules or
vesicles. Molecules that are not stored are produced on demand.
For molecules that are stored in vesicles, their release is triggered by the depolarization of the membrane,
known as action potential. This step may be controlled by modifying proteins required for exocytosis in neurons
NQRZQDV61$5(SURWHLQVWKXVSUHYHQWLQJWKHYHVLFOHV¶IXsion with the cell membrane and subsequent release of
neurotransmitters. Receptors are protein structures to which signalling molecules, known as ligands, bind in order
to elicit a response. Different types of receptors exist; two examples include ion-gated nicotinic channels and
muscarinic receptors. Muscarinic receptors fall under the category of G-protein coupled receptors (GPCRs). These
receptors are activated by a bound ligand, which in turn activates the enzyme adenylyl cyclase. This process leads
to the production of a secondary messenger that initiates a series of enzymatic steps, resulting in response
amplification. In essence, GPCRs are signal transducers.
Finally, after a response has been elicited, the effects are terminated by either enzymatic degradation of the
ligand or its cellular reuptake. Responses can be prolonged by inhibiting the enzymes that degrade signalling
molecules. As enzymes are proteins, they can also be controlled at the genetic level, for example, during
transcription or translation.
It was originally theorized that one molecule binds to one receptor, and the response is proportional to
receptor occupation. This is known as the Clark Occupancy Model. Ligands differ from one another in potency and
efficacy. Potency is the concentration of a ligand required to elicit a certain response. Efficacy is how great the
maximum response of the ligand is. Drugs that have a higher affinity stay on the receptor longer. When a ligand
binds to a receptor to elicit or enhance a response, it is known as an agonist. However, when the ligand inhibits a
response, it is known as an antagonist. If the antagonist is competitive, its effects can be surmounted and the
maximum response can be elicited. A noncompetitive antagonist prevents the agonist from binding to the receptor,
and therefore has a permanent effect. Both agonists and antagonists may bind orthosterically ± that is, to the same
site as the ligand ± or allosterically, to a different site on the receptor, and cause a conformational change. However,
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known as the Modern Receptor Theory.
The Modern Receptor Theory acknowledges the phenomena of spare receptors and partial agonists. Spare
receptors elicit a full response without ligands binding to all of them, whereas partial agonism cannot elicit the
maximum response even with all receptors occupied. An additional complication addressed in the Modern Receptor
Theory is the equilibrium between the active and inactive forms of a receptor. Inverse agonists bind to the inactive
form of a receptor, thus shifting the equilibrium to the inactive form. Furthermore, constitutive activity occurs when
a response can be elicited even when no receptor binds to the ligand. Ligand-binding interactions have the potential
to produce both cellular and physiological effects.
Autonomic tone is one of the last topics you will cover. You will learn that organs are controlled by two
distinct systems: the sympathetic and parasympathetic nervous systems. Under normal conditions, some organs are
controlled by both systems, with the mRUHSUHYDOHQWRQHUHIHUUHGWRDVWKH³GRPLQDQWWRQH´,IWKHGRPLQDQWV\VWHP
is suppressed, the effects of the less dominant system become visible.
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his eyes open, because you never know... he might be giving you a lecture in a coma.
We hope we have provided you with some insight on what to expect next year! H ave fun and good luck!
A Difficult Concept E xplained
Health Scis, one conundrum that you may find more difficult than figuring out who Leroy is, LV³LQYHUVHDJRQLVP´.
This was one of the hardest concepts we came across. Initially, it was difficult to grasp because most of us were
XVHGWR&ODUN¶V2FFXSDQF\0RGHOZKLFKLQYROYHVWKHLGHDRI³RQHPROHFXOHRQHUHFHSWRU RQHPROHFXOHUHFHSWRUFRPSOH[´7KLVLGHDLVRIWen taught in high schools, which influenced us to think that receptors (which
are proteins) had only 1 possible conformation. So naturally, the notion that receptors change conformations,
and multiple forms of a single receptor exist at any given time, seemed incomprehensible.
An agonist binding to a particular form of a receptor can induce other forms of the receptor to become like the
first form. For example, if a ligand binds to the active form a receptor, the inactive forms will transform into
active ones. Inverse agonists bind to the same receptor as an agonist, but induce an effect opposite to that
agonist.
As a group we came to understand inverse agonism through Le ChatHOLHU¶VSULQFLSOHZKLFKZHlearned
in Grade 12 Chemistry. Remember, the principle states that equilibrium must be maintained. In this case, it is
the equilibrium between the active and the inactive forms of a single receptor. When agonists bind to the active
form of a receptor, they shift the equilibrium towards the active state. Inverse agonists bind to the inactive form
of a receptor and shift the equilibrium towards the inactive state.
Confused? Just remember that aFFRUGLQJWR/H&KDWHOLHU¶VSULQFLSOHLIDFHUWDLQUHDFWDQWLVUHPRYHGWKH
equilibrium will shift in favour of that reactant in order to replenish what is gone and re-establish the balance.
Take a look at the illustration below. (A 1:1 ratio for active : inactive ratio is used to illustrate equilibrium)
Inactive Receptors
A ctive Receptors
Description
1. For every receptor, there are two forms (inactive & active ). They
coexist at the same time, and are kept at a state of equilibrium.
2. An agonist binds to an active receptor. This binding elicits a
particular response. This active receptor becomes a new complex once
the agonist binds. Therefore, there are fewer active receptors available.
3. To compensate for the lack of active receptors, inactive receptors
change their formation to become active. This occurs in order to
maintain equilibrium.
4. This logic can be used to understand inverse agonism. An inverse
agonist binds to the inactive form of the receptor. This binding elicits
the opposite effect of the agonist binding to the active receptor. This
inactive receptor becomes a different complex once the inverse agonist
binds. Therefore, there are now fewer inactive receptors present.
5. To compensate for the lack of inactive receptors, the active receptors
change conformation to become inactive. This occurs in order to
maintain equilibrium.
With more inactive receptors created, the probability of inverse agonists binding to the inactive receptor increases. If
more inverse agonists are binding to the inactive receptor, then the response which it elicits becomes greater than the
response of the active receptor. Furthermore, as the inverse agonists bind, there are less inactive receptors available,
and so the equilibrium shifts as explained above. This further exaggerates the response of the inactive receptor.
Eventually, if inverse agonists are continually added, only the inactive receptors' response will be elicited. Therefore,
inverse agonists can "act like an antagonist" because they stop the expression of the active receptors response; however
they are unlike "a typical antagonist" because they also express the opposite response of the active receptor.