Intro Slide (We Don T Have)

Fundamentals

9_25 10-11

Dr. Theibert

Intro slide (we don’t have)

·  Talking about signal transduction, some new material, some review, some you have already seen

·  2 types of slides – FYI slides and a lightning bolt slides. The lightning bolt slides are the material that I am going to expect you to read over carefully and learn. FYI is just to put the signaling in context for the lightning bolt slides.

·  YOU WILL NOT BE TESTED ON ANYTHING FROM THE LIGHTENING BOLT SLIDES

·  She talks about herself and her research interests (incase you care, 1:05 – 1:58)

Slide 1: Why do cells need to signal?

·  Why do cells need to signal? It is very important during development, for cells to divide, to regenerate. Critical in programmed cell death and cell differentiation, i.e. how a neuron becomes a neuron, how to know where it’s going in developing and how to send out its processes.

Slide 2: Adult FYI slide

·  It’s also important in the adult for maintaining homeostasis, detecting information and transducing that information from the environment, from the internal as well as external environment and generating behaviors.

·  In the nervous system it is essential for detection information such as light, all the different senses and generating behavior based on changes in muscles.

Slide 3: Why study signal transduction

·  So how do we know so much about signal transduction?

·  As scientists we are interested in how organisms work but we also know now that disruption of normal signaling underlies a number of different diseases.

·  Example, in diabetes type I, we know that insulin is not made or synthesized and released properly, in type 2 we know that cells do not respond to insulin normally.

·  In many different diseases, there is too little cell signaling. In addition to diabetes, this includes anemenia, neuropathy, and osteoporosis.

Slide 4: Disease of cell signaling

·  In several diseases there is too much cell signaling.

·  Example: in cancer, there is unregulated cell growth.

·  Also seen in retinopathy, cardiovascular diseases. There is an excessive amount of cell signaling that underlies these.

·  As basic scientists, we want to know how the body works and how different organisms function.

·  As clinical related and translational scientists, we want to know what is corrupted in cell signaling that underlies these different diseases.

Slide 5: Two Types of Signaling for Cell-to-cell Communication, Direct-Gap Junctions, Indirect-Receptors and Signal Transduction

·  So you have heard of over the last few days about some processes of signaling.

·  Quick step back and mention that there are actually 2 types of cell signaling for communication.

·  Direct signaling involves gap junctions and then there is indirect signaling.

·  I only have one slide about gap junctions.

·  Cells actually have the ability to signal to each other directly.

·  The rest of the talk today will focus on signal transduction, and in signal transduction, there is the conversion of one signal to another.

·  What you have been hearing about for the past few days is the conversion of chemical information into a change in chemical information inside the cell. I will continue this.

·  Important to mention that there are actually many different types of signal transduction involving :

o  Change in electrical signals into chemical signals

·  If you have studied neuroscience, you know that this is the basis of one of the major ways that neurons signal to other neurons.

·  You have an electrical change in a depolarization which is converted to a chemical signal at the synapse and which can then be converted back into an electrical signal in the post synaptic cell.

·  In addition, there can be physical signals that are detected and changed into chemical signals.

·  For example, the mechanotransduction which occurs in the skin – your pressure and touch receptor convert physical signals to chemical signals within the cell.

·  Can also be chemical signals converted into physical signals at the neuromuscular junction.

·  Acetylcholine, a chemical signal, is converted into muscle contraction. This involves signal transduction as well.

·  Rest of the talk will focus on chemical to chemical signaling.

Slide 6: Direct signaling

·  In direct signaling, it is a very ancient type of signaling involving gap junctions.

·  Occurs when there is physical connection between cells.

·  Quite widespread – a few years ago we used to only think it was used during development, but for example, the glial cells in the brain (astocytes) are coupled to each other this way.

·  This type of signaling involves the direct transfer of a molecule from one cell to another.

·  Does not involved signal transduction and it can be extremely rapid because the signal diffuses

·  The rate limiting step is the diffusion of the signal from one cell to another

·  Thought to be involved in coordinating groups of cells that are physically connected to one another

·  Not a very useful type of cell signaling when you have a multicellular organism because (2 reasons) only small molecules can pass through. Limited in terms of the type of molecules that can be transmitted and cells have to be right next to each other because cells have to be in direct contact.

·  A lot is known about the molecules that mediate this – they are the gap junctions. They are a type of channel formed on either side of the cell. Very large proteins; form a pore very similar to an ion channel.

·  Pore is actually contributed to by both sides of the cell.

·  Made up on connexin proteins, which are very similar to ion channels.

·  Very limited, not only because they have to be between cells in direct contact, but also because there is no mechanism for amplification of the signal.

·  The signal just diffuses from one cell to another, so it cannot be amplified so it eventually runs down.

·  It is not very adaptable; there is no way to convert that signal into any other type of signal.

·  Its very important we know gap junction are very important; they are essential in development,

and are used in very rapid responses, such as escape responses in fish.

·  We really don’t know much about the function of gap junctions of the adult.

Slide 7: Signal Transduction: Converting extracellular signals into intracellular responses

·  Signal transduction, on the over hand, is the conversion of extracellular signals into intracellular responses. This is very adaptable. It can be amplified and underlies the majority of signaling between different cells and other adjacent cells in the body.

·  You know that extracellular signals work through receptors. The signals can be very different in nature.

·  They can be very different in their chemical makeup.

·  They can either be small molecules, proteins or hydrophobic molecules. They can be working at short distances or at long distances.

·  In general, these molecules are somehow secreted by the cell that is doing the signaling and there is a receptor on the target cell which interacts with the molecule being released.

Slide 8: Ligand: any molecule that binds to a receptor

·  Just a couple of definitions that we use.

·  We talk about ligands in pharmacology – a ligand is any molecule that can interact with a receptor.

·  There are endogenous and exogenous ligands.

·  Endogenous ligands are the molecules that we synthesize in our bodies and they are the molecules that do the signaling.

·  The exogenous ligands are molecules that can be synthesized in plants or in the laboratory; exogenous ligands include drugs.

·  There are two different kinds of drugs that either activate or enhance responses or block responses.

·  In general, agonists are ligands that bind to receptors and activate or enhance a response

·  An antagonist is a molecule that binds to receptors that either inhibits or blocks a response. Does not activate a response.

·  Exogenous ligands can be very different in their chemical natures.

·  There are hydrophilic ligands (these are water soluble) and they cannot pass through the cell membrane so they have to work by binding to an activating cell surface receptor.

·  Then there are hydrophobic ligands (lipophilic, water soluble) ligands. You heard about steroids, and these types of ligands (hydrophobic, can pass directly through the plasma membrane, have access to the inside of the cell. Usually work through intracellular receptors, but there are a few hydrophobic ligands, in addition to intracellular receptors, also have some cell-surface receptors.

·  Often, ligands don’t really require any signal transduction per say. Their receptors are the target, which activate the response.

·  For example, the estrogen receptor inside the cell binds estrogen. The receptor is itself a transcriptional regulator.

·  There is nothing that is being converted; the only conversion is the movement of the ligand into the cell and the activation of the receptor itself.

·  Endocrine signaling – signaling works on many different time scales. You learned about endocrine signaling which is usually pretty slow.

·  Its activation and response is on the order of minutes to hours and a lot of slower regulatory processes are regulated in the endocrine system.

·  You have heard about steroid hormones and growth factors like insulin. These regulate things like cell division, proliferation and development.

·  But signaling can also occur very quickly on the order of milliseconds in neuronal transduction and the order of seconds in other sensory responses like vision, metabolic responses to insulin and also in the cardio vascular system.

Slide 9: The Process of Cellular Communication

·  There are 5 major types of processes that are involved in all signal transduction activities.

·  In this, the signal in the first step, the signal is synthesized (you heard about peptide hormones and steroids in the last couple of days).

·  The signal has to be synthesized by the cell that is making and releasing the signal.

·  Next, the information has to be detected. This occurs through the receptors.

·  The third step is where the conversion of this signal takes place. It is being converted from one signal outside the cell into a different kind of signal inside the cell.

·  Usually this involves protein phosphorylation or the production of second messengers.

·  Then you have the modification of cellular activities. These are the proteins and the activities that are downstream of the 2nd messenger.

·  This leads to changes in things like metabolism, gene expression, protein expression, changes in the morphology of this cell entering in the cell cycle.

·  The last stage, the signal has to be terminated. For some ligands, the signal is actively terminated so there are transporters that take up the signal or enzymes that degraded the signal.

·  For things like steroid hormones and peptide hormones, those are usually end up being cleared through different processes taken up through the liver and other organs.

Slide 10: Endocrine Signaling

·  Just a quick review – endocrine signaling. You have heard all about this the last couple of days.

·  Endocrine organs release hormones. The hydrophobic hormones are usually carried by the blood via carrier proteins; hydrophilic hormones(like insulin) they are water soluble so they DO NOT NEED a carrier protein.

·  These hormones get diluted into the blood and the dilation is great.

·  So you have a little organ which is making some hormone and it is getting diluted into this very large concentration of the blood.

·  The concentration of these endocrine hormones is usually very low; means the receptors that bind to these hormones have to have very high affinity.

·  Steroid receptors and insulin receptors have affinities on the order of 10-9 which means they can detect picomolar concentration of hormone in the blood.

·  In the endocrine signaling, you know that the target is usually another cell in a different organ.

·  The target cells are working at a distance from the endocrine organs.

Slide 11: Endocrine Organs and Hormones

·  You have heard about endocrine organs and hormones - skips

·  You already learned about steroid hormones.

Slide 12: Examples of hydrophobic (lipophilic) hormones

·  Skip - these are fyi slides (read over in context of the lecture)

Slide 13: Examples of small molecule hormones

·  In addition to the steroid hormones, there are small molecule hormones.

·  These include things like epinephrine, aka adrenaline, histamine, glutamate. These are small molecules that are used by endocrine organs.

·  They are released into the blood and molecules like epinephrine, for example, which is involved in the fight or flight response, is released from the adrenal medulla.

·  It acts on the cardiovascular system, the heart. It has a lot of different target cells.

·  Histamine is made in mast cells; it is released and leads to dilation of blood vessels and mediates many of the inflammatory response.

Slide 14: Small molecule hormones, Amino acid derivatives

·  Small molecule hormones are small chemical molecules. They are small chemical molecules. They have to be packaged into vesicles before they can be released by the endocrine cells.

·  They are pumped into specialized secretory vesicles shown here.

·  This is a neuro sectretory cell. There release is regulated by another hormone or another activity.

·  It requires calcium for these vesicles to fuse and release this small molecule out into the blood.

Slide 15: Examples of peptide hormones

·  In addition there are peptide hormones which work in the endocrine system.

·  You heard about glucagon and insulin; these are small peptides. They are 20-50-80 amino acids which are made by specific endocrine organs.

·  Glucagon and insulin are involved glucose regulation and fat regulation. You also heard about other hormones like luteinizing hormone which are made neurosecretory cells and regulate a number of different reproductive activities.

·  Peptide hormones are proteins. They have to be synthesized in the ER. They are polypeptides synthesized in the ER, trafficked to the Golgi and are packaged in the Golgi into secretory vesicles.