Course

Introduction

Welcome to HTHSCI 1I06! This course will be different from anything you have done before.
OK, not a huge leap, since this is likely one of your first classes in university. However, you
will be doing things differently than you might expect. We will be introducing you to some
information relating to cell biology, but will use a very specific approach to provide a
framework for your learning. You will need to be active in the process of learning, reading
things on your own to better understand things you are curious about.

The first thing you must do is to actively read and understand the course outline. If you are
going to ask us a question that is answered already in the course outline, we might not
respond.

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 Name Email
Haram Akram akramh11@mcmaster.ca

Atai Ariaz ariaza@mcmaster.ca

Frass Chaudhary chaudf13@mcmaster.ca

Aidan Gagnon gagnoa8@mcmaster.ca

Vitoria Olyntho olynthov@mcmaster.ca

Parsa Razeghi razeghip@mcmaster.ca

Nancy Paris Rosen rosenn2@mcmaster.ca

Julia Sharobim sharobij@mcmaster.ca

Rudra Sheth shethr4@mcmaster.ca

Allison Tomashewski tomashea@mcmaster.ca

Kian Torabiardakani torabiak@mcmaster.ca

Mika’il Visanji visanjim@mcmaster.ca

Here are the TAs and their email addresses. We will be posting a class list with TA
assignments before Thursday. You need to find your TA and go to their location on Thursday
at 2:30. The TA group assignments are not negotiable.

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Object
Lesson

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 TAs to divide room into sections

TAs will take sections of the room and will hand out some objects for you to have a
discussion with your peers and the TAs. After some time, we will start asking for some of
your thoughts on the objects provided.

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 Health Sciences 1I06:
Cellular and Molecular Biology

Lecture 1:
Signalling
P. K. Rangachari
Eric Seidlitz

Signalling becomes the cornerstone of this entire course. Signalling is so fundamental that
it can be applied equally as a framework to understand how cells function or even to how
social systems operate. Here, we will focus on the cellular communication processes that
lead to (or correct) health disruptions.

Cartoon drawn by Harnish-Secord Group 2, Dec 2013.

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In this course, we are going to be exploring signalling in a cell biology context. Although
the general principles of communication systems apply in all cases of the movement of
information, we have chosen to focus on two arbitrary levels of analysis – the signalling
between cells and the signalling within cells.

The genomic signalling processes within cells (shown on the left) involve the familiar
structures of DNA, RNA, and proteins. We will talk more in future lectures about the
processes that move information between each of these structures and how their
functions are regulated. On the right are the general communication steps that we will
apply to signalling that happens between cells.

Although these cascading pathways have been drawn in a way that suggests that they are
separate events, they are quite interrelated. In some ways, the genomic events on the left
underlie each of the steps that are shown on the right. Equally, the communication steps
on the right also apply to each of the genomic events. However, they are quite effective
model systems that help us understand the complexities of cellular signalling. We’ll start
with the concepts relating to communication between cells and build up to more specific
examples.

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If we consider a signalling event from one cell to another using a generic messenger
molecule, these are the fundamental communication steps that are usually involved:

1. The generic signalling molecule needs to be produced in some way.

2. The molecule is sometimes packaged for later use.
3. The molecule is released from the sending cell and travels to the
target/receiving cell.
4. The molecule is detected by the target cell and a response is generated.
5. Finally, the molecule itself is terminated to ensure that the signalling event
ends.

If you apply this framework to any signalling event, you can see how each step is an
opportunity waiting for things to go wrong.

Question: What is the big deal with these steps? Why are they so important? Can I pass
without knowing them inside out?

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 Diabetes
Lupus
Coronary artery disease

Allergies/asthma

Anxiety/depression
Glaucoma

ADHD
Signalling GERD
gone wrong
Hypertension
Cystic fibrosis
Cancer

Crohn’s/colitis
Cholera
Rheumatoid arthritis

So, why are we looking at communication in the first place? Problems with cellular
signalling can be viewed as critical to the development of many diseases. With such an
array of diseases relating to signalling that has gone wrong, you can begin to see why a
solid understanding of cellular signalling might be important.

To begin, let’s go back and discuss the general principles of cellular communication.

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 General principles of
cell-to-cell communication
• Framework
• The right signal
• The right reception
• The right response
• A stop, somehow

• Focus on
• The signalling cell
• The target cell

For cell-to-cell communication to work correctly, you need to have the right signal
transmitted, the right reception of that signal, the right response to the signalling event,
and some way to stop the signalling so that it doesn’t continue eliciting the response
indefinitely. If all of these parts of the framework come together, cell-to-cell
communication may occur. In this context, we will focus on both the signalling cell and the
target cell, as both are critically involved in the process of communication.

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 General features of any signalling molecule

• Must be produced (in advance/on demand)

• Must be released (storage is optional)

• Must elicit a response

• Must have its actions terminated

If you consider a generic signalling molecule, it must go through a series of conceptual

steps. It must first be produced (whether this is done in advance or at the time the
molecule is needed depends on the specific of the system involved), it must be released to
move to the target cell (it may be stored for release when needed), it must elicit a
response, and the actions of the molecule need to be terminated. This is the basic
framework for signalling that we have given you a few slides ago. Always keep these in
mind, as these steps are the best way to tease apart a cell communication system to better
understand how things work (or don’t work).

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 Types of signalling

There are many types of signalling that occur between cells. We will talk about some of the
basic categories of signalling, but will separate them by the distance between the sending
and receiving cells.

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 Relative locations of signalling and
target cell determine
distance travelled/stability of
messenger molecules

This statement may seem obvious to you, but when you think about it, the concept of the
distance between communicating cells and how durable the signals are is critical to the
success (or failure) of a communication system. Different types of signaling have different
characteristics, but one way in which they can be broadly categorized is by the relative
distance between the signalling and target cells.

Think about using your cell phone. You probably instinctively know that being close to the
router or access point is a good way to improve the wi-fi or cell tower signal. However, is it
simply distance that is important in this case? When you don’t have wi-fi, how many of you
find yourselves walking around with your phone trying it to show more bars at the top of
the screen? What about the position of your cell phone with respect to the walls, windows,
roommates, etc.? How about when everyone is streaming 4K video at the same time?
Seems that you also instinctively know that the signals can be interfered with or can’t pass
through certain materials as well as others.

This is the main concept we are getting at here: if you want efficient signalling, you must
consider the distance needing to travel (and consider what is in the way) and the stability of
the message itself. We will talk about many different examples of cellular communication
systems, so always keep in mind these important issues. If it helps to use an analogy like a
cell phone, go for it! The signalling concepts are the same, regardless of the components
that are involved.

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 Shorter distances
AUTOCRINE = communicate with same cell

PARACRINE = communicate with nearby cell

Starting with shorter distance signalling (where the distance travelled is often very limited),
common examples are gap-junctions, contact-dependent, and autocrine types. If a cell
signals to itself, it is an autocrine signalling event. If it signals to another cell (whether it is
the same type of cell or not), that is a paracrine signalling event.

Question: Can a cell have gap junction or contact dependent signalling that is autocrine?
Let us know what you think and why.

Several of the figures used in this section are used with permission of Dr. Silverthorn. Dee
U. Silverthorn (2013). Human Physiology: An Integrated Approach. Sixth edition.
https://amzn.to/2KZ1w24

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 Longer distances

• Generally slower
• May require a way to stabilize far-travelling
signalling molecules

Moving into much longer distance communication, two good examples are endocrine and
nervous system signalling. The signalling cell is typically at great distances from the
receiving cell. These types sometimes overlap.

Question: Why does distance matter?

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 Endocrine

Endocrine signalling occurs when one cell releases a molecule that will then be received
and elicit a response in a distant cell. In most cases, the signal must travel through the
blood stream to reach the target cell. Considering that the volume of blood that a signal is
dumped into from the sending cell can be very large, the receiving cell must be exquisitely
sensitive to the signal for a response to occur. Endocrine signals can sometimes be
hormones, but not always.

Question: What does the fact about going through the blood stream imply with regards
to the signals or the receivers of the signals?

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 Neuronal

Neuronal communication can be somewhat more difficult to understand, as there can be a

combination of signalling types involved.

Sometimes the neuron is the cell that produces the signal but the target cell can be very
close to that neuron (an example here would be a muscle responding to acetylcholine
signals which make the muscle contract). They can also be further away, where a neuron
releases a signal that acts in a more endocrine fashion on a distant target cell. The signaling
processes within neurons are often quite specialized, and can take the form of chemical
signals as well as electrical.

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 Synaptic

Synaptic signalling is a unique type of communication that occurs at a specialized area on

neurons. These areas allow for a rapid local release of signal molecules to communicate
with very close by adjacent neurons.

Question: Are synapses only able to communicate one direction, from sending cell to
receiving cell?

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 Signal transduction

Many of the scientists who developed our notions of cell signalling mechanisms ( Hodgkin,
Huxley, Crick, Kendrew ) served in the military during the Second World War, several as
radio operators. They used analogies drawn from that world (where radio communications
were crucial ) in looking at cellular communication. Martin Rodbell, in particular looked at
cells having receivers, transducers and amplifiers in responding to received information.
Signals were sent into the ether ad only carefully tuned receivers responded, changing the
gain made weak signals prominent, so amplification was crucial.

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 + termination!

This is the same signal transduction pathway but shown in the context of cellular
structures. The concepts are the same, even if the components are different.

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Cildo Meireles, “Babel”, 2001 (Tate Modern) https://www.tate.org.uk/visit/tate-modern

“Babel 2001 is a large-scale sculptural installation that takes the form of a circular tower made from hundreds
of second-hand analogue radios that the artist has stacked in layers. The radios are tuned to a multitude of
different stations and are adjusted to the minimum volume at which they are audible. Nevertheless, they
compete with each other and create a cacophony of low, continuous sound, resulting in inaccessible
information, voices or music. In describing this work, Meireles refers to a ‘tower of incomprehension’ (quoted
in Tate Modern 2008, p.168). The installation manifests, quite literally, a Tower of Babel, relating it to the
biblical story of a tower tall enough to reach the heavens, which, offending God, caused him to make the
builders speak in different tongues. Their inability to communicate with one another caused them to become
divided and scatter across the earth and, moreover, became the source of all of mankind’s conflicts. The
room in which the tower is installed is bathed in an indigo blue light that, together with the sound, gives the
whole structure an eerie effect and adds to the sense of phenomenological and perceptual confusion. The
radios are all of different dates, the lower layers nearest the floor being composed of older radios, larger in
scale and closer in kind to pieces of furniture, while the upper layers are assembled from more recent, mass-
produced and smaller radios. This arrangement emphasises the sense of perspectival foreshortening and thus
the impression of the tower’s height, which, like its biblical counterpart, might continue into the heavens.”
https://www.tate.org.uk/art/artworks/meireles-babel-t14041

Not sure how radios work? Students in a previous year’s class came up with a more post-
millennial kind of explanation.

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 Instagram Metaphor

This was from the group “Dominic 3” from 2021-22.

Thank you Maya, Sanduni, Tasfia, and Andrew!

This was from the group “Dominic 3” 2021-22.

“The problem we faced with this concept was largely attributed to the outdatedness of the analogy
used in class. Our professor, Dr. Rangachari, being the wise and experienced teacher he is, gave us
an example of signal transduction through the analogy of radio waves converting into sound waves.
This example, while fulfilling our daily quota of a new fact per day, caused increased confusion due
to our lack of knowledge of radio systems. Bearing in mind the nature of the Gen Z world, we
composed an alternate analogy for signal transduction that revolves around a social media platform
–more specifically, Instagram. This social media platform allows the users to communicate and
share media through posts while also reacting to ones made by others. Sharing, liking, and/or
commenting boosts the popularity of the post increasing its exposure on the platform. On
Instagram, all users have an account more commonly referred to as their profile which they can use
to “follow” other profiles –an act of communication. Our analogy will consider Instagram as a
tissue, with defined intracellular spaces consisting of profiles acting as biological cells and an
extracellular domain represented by the explore page that connects these profiles. Similar to a
cell’s receptor, profiles have a mechanism that demonstrates selectivity –the follow button. A user
can choose which follow request is accepted into their private profile, which parallels how
receptors accept only some molecules, allowing those who fit within their criteria to interact with
their posts. After being accepted, a change occurs. The signal turns from a stranger to a follower –
who has more accessibility to a profile– allowing them to interact via likes, comments, and shares.
These interactions can be compared to the amplification process during cell signalling since the
secondary actions boost the visibility of the post to other followers, thus allowing for a vicious
cascade where one like is transformed into ten likes, then hundreds and, if lucky, millions. These
signals alert the user’s cell phone through notifications on their profile, mimicking a cellular
response (see figure). With this analogy, you can understand how a foreign signal can use
mechanisms adopted by a cell to change it into one that is familiar, and then amplifying it to later
produce a response.”
Again, look at the concepts, not at the details. Concepts will help you to understand what happens.

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This is the same processes in the cell, drawn to give you a better picture of where these
communication system structures may be located.

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Receptors can be in many different locations, not always on the cell surface. The location of
the receiving structure for a given signal molecule helps to define some of the features of
that signal molecule. If the receptor is on the inside of a cell, only molecules that can get
into a cell (alone or with a partner molecule) will be capable of being received.

Question: If a signal molecule needs to reach a receiving structure on the inside of a cell,
what does that suggest for the properties of the signal molecule?

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The events which occur under the cell membrane after a signal molecule (a ligand) meets
with the receiving structure (a receptor) allow for amplification of that single signalling
event into a larger number of molecules being involved that eventually comprise the
cellular response. Later lectures will go over more details.

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There are many different types of receptor systems on cells, some of which we may not
cover in this course. These receptor types have specific features that provide some
advantages for different signalling environments/contexts.

Question: Do we have to know all of these receptor types?

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Where the components of a signalling system inside a cell are located is something to
consider when studying signalling. The locations could be very important when trying to
understand when signalling fails (then you can hypothesize what structures may be
involved in the failure).

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Nature’s economy – single molecule can be used to amplify a signal. The message may go,
but the response can linger. Time is the key – some chemical processes will occur over
extended time periods to amplify signals.

Consider the old story of ‘telling something to one friend, who tells it to two other friends,
who each tell it to two others…’. That amplification of the signal doesn’t take into account
that the first person may be a prolific gossip and is able to tell 10 others before they get
bored, the second level of people could tell hundreds (they maybe use X) or thousands
(they maybe use Instagram). See how time or durability of a chemical process can be
important to how this all works? Signalling can involve many components (chemicals,
electrical impulses, proteins, etc.) and each component can have an inherent stability that
can determine the success or failure of getting the message across.

Question: Why do communication processes that involve making a protein seem to last
longer than those that involve releasing a stored amine (like at a synapse)?
 PATHWAYS—NETWORKS

One of the more intriguing concepts that emerges out of signal transduction pathways are
the series of networks. For instance, here are shown three different pathways.

• In one case, one molecule binds to a receptor to activate two independent pathways
which can trigger two different responses.
• In another, two molecules bind to different receptors yet activate a single pathway.
• In the third, two molecules bind to different receptors and activate different pathways,
yet the pathways themselves interact.

These pathways can be extremely complicated, so teasing out these networks has become
crucial to understanding how cellular signalling works.

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 Response

Dose

This concept (the dose-response curve) is critical to many parts of the course.

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 Importance of dose-response curve

https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacodynamics/dose-response-relationships

Dose-response curves are derived from testing a biological response to a stimulus with a
range of doses of that stimulus. You perform multiple tests over that range and plot the
responses observed against the dose of the stimulus (usually with a logarithmic scale for
dose). The characteristics of the resulting curve can be used to infer how the stimuli and
responses are related.

Note: A dose-response (D/R) curve is not a single response. It is multiple responses that are
then used to derive the curve.

Learn more about dose-response curves:

https://study.com/learn/lesson/dose-response-curve-effect-examples.html

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Demo of Organ Bath software

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 Generating a concentration-response curve

G H I

D
A B C

Standard approach : tissues set up in organ baths and drugs added ion increasing
concentrations. Each time the response increases and then plateaus—that represents the
equilibrium attained at that specific concentration; the rate at which molecules “occupy”
the receptor balanced by their tendency to leave it. Once that is attained, the next
concentration is added. The plateau value at each concentration is used to construct the
curve.

The University of Strathclyde in Glasgow has prepared several useful pharmacological

simulation apps. These can be found here:
http://spider.science.strath.ac.uk/sipbs/software_sims.htm

Version 4.1 is now available for both Windows and MacOS at:
https://github.com/johndempster/ObSimFMX/releases/tag/V4.1

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 Example signalling molecules
• Amines
• histamine, noradrenaline, dopamine, serotonin, acetylcholine
• Lipophilic mediators
• corticosteroids, estrogens, androgens, prostaglandins,
cannabinoids, etc.
• Small molecules
• gases (NO, CO, H2S), H2O2
• Peptides
• bradykinin, substance P, etc.
• Polypeptides
• insulin, gastrin, etc.

Here are several examples of different categories of molecules used in cellular signalling.
We will pay more attention to the ones highlighted in red.

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 Building blocks of all cellular communication
processes are inside the cell

• Signal molecules
• Release mechanisms
• Receptors
• Response systems http://bptba.lipi.go.id/bptba3.1/?u=blog-single&p=404&lang=id

• Termination mechanisms

It is important to understand that the building blocks for all of these cellular
communication processes are INSIDE the cell. This is where the understanding of the
genomic system is becomes very important to the understanding of all cellular signalling.

This is also the reason that a significant part of this course focusses on the molecular
processes leading to all the receptors, enzymes, and signalling components that you will
learn about. All of the structures used in cell communication have their origins inside the
cell and are reflections of coded information in the genomic system. To understand how
cells communicate, you must understand how cells generate the structures involved in the
communication process.

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We will be using this framework throughout the remainder of the course. If you can keep
always these abstract communication steps in the back of your mind, you will have a much
better chance of seeing clearly what directions to go when solving any kind of problem of
cellular communication.

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 Structural Functional

Is more BHSc_amine present

Is BHSc_amine present?
under condition y?

Is the enzyme present that How does the activity of the

allows for BHSc_amine BHSc_amine synthesis enzyme
synthesis? change over time?

Are BHSc_amine containing Are the granule contents the

granules present in the cell? same after doing y?

Is BHSc_amine released from How many granules remain after

granules? treatment with y?

What happens when

Are BHSc_amine receptors
BHSc_amine receptors are
present?
blocked?

What happens to response when

Is a BHSc_amine degradation
BHSc_amine degradation
enzyme present?
enzyme is not present?

In the context of a BHSc-amine-releasing cell, these are example questions that can be
asked at each communication step. We will be including methods throughout our lectures,
but please don’t get hung up on specific methods. The methods are only relevant within
the context of the question that is being asked with the method.

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 Structural Functional

If the gene for BHSc_amine

Is the gene for BHSc_amine
receptors is mutated, how does
receptors present?
the cell response change?

How does the level of the mRNA

Is the gene for BHSc_amine
for a BHSc_amine synthesis
receptors expressed as mRNA?
enzyme change over time?

Is the mRNA for BHSc_amine

Is there less mRNA present for
receptors present in the
BHSc_amine receptors after y?
cytoplasm?

Are nascent BHSc_amine What happens when translation

termination proteins found in of BHSc_amine receptor proteins
the Golgi? is interrupted?

Are BHSc_amine receptor

Are there more BHSc_amine
proteins present on the
receptors present after y?
membrane?

You can look at the genomic communication system and ask very similar questions that are
structural and functional. There are typically many ways to answer structural and
functional questions, and the same test could easily be used for both types of question – it
just depends on how you set up the system when you are applying the method.

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 Essential elements
• Communication steps
• Cell to cell
• DNA to protein
• Cell signalling terms
• Autocrine / Paracrine
• Endocrine / Neuronal
• Synaptic
• Signal transduction and amplification
• Receptors and their locations
• Signal transduction pathways
• Dose-response curves
• Genomic basis for molecules
• Structural/Functional approaches (general)

These are the essential elements to understand from this lecture.

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 REFERENCES
A number of the images shown are taken from the
following sources:
• Silverthorn, Dee U. (2019). Human Physiology: An Integrated
Approach. 8th edition. Boston: Pearson. https://amzn.to/2KZ1w24

• Hardin, J., Bertoni, G., Kleinsmith, L. J., & Becker, W. M. (2015).

Becker’s World of the Cell. 9th edition. Boston: Pearson.
https://www.amazon.ca/Beckers-World-Cell-Jeff-Hardin/dp/032193492X

Many similar resources are available to you free of charge through the university library
system. We don’t recommend that you buy any textbooks (they tend to be out of date even
if new). We would far prefer that you seek out the best information sources for the work at
hand, particularly by looking at the scientific papers that originated the ideas.

The library website is your friend. If you don’t know how to find things on your own, you
will be left behind. Yes, high school is over.

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 TA Meeting locations

Atai Aidan

Kian Frass Mika’il Haram

Allison

Vitoria Parsa
Nancy
Julia Rudra

You will meet with the TAs in these locations at 2:30 to 3:30 on Thursdays.

After your TA sessions, you will return to the main classroom (1A1) at 3:45 for an
instructor-led Q & A session.

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