Cell Communication

I. General Info

A. What is cell communication? Cells talk to each other using chemicals. Some of the things cells might say to each other include: i. Are we sexually compatible? Ex- type alpha and type a yeast ii. How many of us are there? Ex- Vibrio fisheri, bioluminescent bacteria that only luminesce when they are crowded together iii. If the cells are part of a multicellular organism, cells talk to each other to alter and coordinate each other’s activity and keep the organism alive. This is what we will focus on! B. In a multicellular organism, cells communicate with chemicals in 3 general ways: i. Synapses- a neuron spits chemicals (neurotransmitters) onto a cell, either another neuron or another type of cell. For example, your muscle cells contract because a neuron told them to. ii. Paracrine communication- cells in a local area can talk to each other. iii. Endocrine communication- cells in one area of the body can talk to cells far away. Chemicals that are used for this type of long-distance communication are called hormones. In animals, hormones travel through the circulatory system. These are the chemicals we will draw our examples from.

1 -from here on out I will refer to chemical signals, whether they are neurotransmitters, paracrine factors, or hormones, as “signals” unless I am using a specific example.- C. A cell can only “hear” a chemical signal from another cell if it has a receptor for that signal. A receptor is a protein that can specifically bind to the chemical signal. Receptors may be embedded into the membrane and stick into the exterior space or may be in the cytosol. Generally, water- soluble signals bind to receptors on the EXTERIOR surface of the cell. These signals do NOT enter the cell. Lipid- soluble signals generally diffuse into the cell and bind a receptor in the cytosol.

II. The action of chemical signals: how they send a

message and how receiving cells respond to that

message

A. What signals cause cells to do: i. Turn genes on: remember that genes generally code for proteins, so "turning on" a gene will cause a protein (such as an enzyme or channel) to be made. ii. Activate or inactivate an existing enzyme or other protein in the cell - Overall, the effects of these actions can: 1. Alter membrane permeability or solute absorption by opening or closing channels (#ii), or causing them to be made (#i) (for example, calcitriol causes the production of Ca2+ channels in cells lining the small intestine, so that dietary Ca2+ may be absorbed; insulin causes the activation of

2 glucose channels so that cells may take in glucose from the blood) 2. Induce secretory activity; for example, by the production or activation of enzymes involved with making products for secretion 3. Stimulate cell division; for example, by the production or activation of enzymes involved with replication of organelles or DNA 4. Alter metabolic activity; for example, by the production or activation of enzymes involved with ATP production 5. Alter the rate of transcription or translation, ie, make particular proteins/enzymes faster or slower.

B. How Water-Soluble Signals work i. There are 3 general types of receptors that can bind to water-soluble signals: 1. Ion channel receptors: these are actually gated channels. When a signal binds to them, they open. For example, when a neuron tells a muscle cell to contract, it spits the neurotransmitter acetylcholine onto the muscle cell. Acetylcholine binds to a receptor on the muscle cell. This receptor is actually a Na+ channel that has been closed. It opens when Acetylcholine binds, and Na+ rushes in. That event will eventually lead to a muscle contraction.

3 2. Receptor tyrosine kinases- more about these later, but an example of a signal that binds this type of receptor is the hormone insulin. 3. G-protein linked receptors- more about these later, but an example of a signal that binds this type of receptor is the hormone epinephrine (adrenaline). ii. How a cell responds when water-soluble signals bind to tyrosine kinases and G-protein linked receptors: signal transduction 1. When a signal binds one of these receptors, the receptor will change shape or move on the INTERIOR part of the cell. This event will set forth a series of chemical reactions that will eventually lead to the activation or inactivation of specific proteins. 2. As stated above, binding of signal to the receptors causes a cascade of chemical events within the cell. In many pathways, the ultimate goal is to activate protein kinases, enzymes that phosphorylate other chemicals (for example, kinases could phosphorylate enzymes that drive the production of thyroid hormones in thyroid cells). Why does this matter? Many proteins are activated or inactivated by the addition or removal of phosphate; so by adding phosphate to proteins, kinases can turn them "on" or "off." 3. The substance that activates the kinases is called a second messenger. Two common second messengers that are used in signal

4 transduction pathways are cyclicAMP and Ca2+. 4. I will ask you to know the events that occur when a signal binds to a G-protein linked receptor using cAMP as a second messenger. I will not ask you to know the events of the tyrosine kinases, or the events that occur when Ca2+ is used as a second messenger. Here’s how the G-protein linked receptor/cAMP system works: First, be aware that there are 3 types of membrane proteins you need to know about: 1) the hormone receptor, which spans the membrane from the outside surface to the interior 2) the G- protein, which is bound to the receptor on the interior portion of the membrane. The G-protein has a molecule of GDP attached to it. 3) Adenylate Cyclase, an enzyme that spans the membrane. Take a minute to draw a portion of the membrane with these 3 proteins. As you read each of the following steps, redraw the pictures, showing what's going on at each step.

Let's use a liver cell responding to epinephrine. One of the things that liver cells do in response to E is break down glycogen to release glucose to the blood (what other hormone has this effect?). When epinephrine binds to its receptor, the receptor changes shape and causes the G-protein to eject its GDP. When GDP is ejected, the molecule GTP takes its place. The G-protein is now activated and released from the receptor.

The G-protein moves along the interior part of the cell membrane once it's released. It will bump into and bind an Adenylate Cyclase.

Adenylate Cyclase, upon being bumped and bound, will drive the reaction: ATP --> cAMP. That is, it will convert ATP to cAMP.

Again, cAMP is the 2nd messenger, whose job it is to activate kinases. So, cAMP cruises around the cytosol, activating kinases. Incidentally, there are enzymes ready to degrade cAMP almost as soon as it's made.

5 Now, we have a bunch of kinases running around really getting the job done: activating or inactivating proteins that will have the effect desired by the hormone. For example, in liver cells, one of the enzymes that gets activated by these kinases is responsible for chopping glucose units off of glycogen chains.

C. How lipid-soluble signals work: these are a little more straightforward. Lipid-soluble signals, such as steroid hormones, diffuse into the cell freely. They will bind with a receptor in the cytosol (or sometimes in the nucleus). Together, the signal chemical and the receptor will go into the nucleus and bind DNA adjacent to specific genes. That binding will cause genes to be activated, and the cell will build more of the target protein. For example, in muscle cells, testosterone activates genes that code for contractile proteins (actin and myosin).

III. Three specific examples of hormone effects on a liver cell’s use of glucose. Some background- when you eat, liver cells store glucose as glycogen. After you fast for a few hours, glucose levels in the blood fall so the liver cells break down the glycogen and put that glucose into the blood. If you fast for several hours to days, the liver cells will build new glucose using other sources, like amino acids. The liver is largely responsible for making sure that there is enough (but not too much) glucose in the blood. What you need to know from this is ONLY the name of the hormone and which type of receptor it uses. The names of the enzymes and their actions are just for your interest!

A. Insulin- when you have just eaten, insulin is released. Binds a tyrosine kinase. A very complex series of activations leads to the activation of protein phosphatase- 1, which will: i. Activate glycogen synthase, an enzyme that builds glycogen ii. Inactivate glycogen phosphorylase- an enzyme that breaks down glycogen

B. Epinephrine (adrenaline)- after a fast, epinephrine is released. Binds a G-linked receptor. Uses cAMP as a second messenger. cAMP activates protein kinase a, which then activates phosphorylase kinase. Phosphorylase kinase will: i. Activate glycogen phosphorylase

6 ii. Inactivate glycogen synthase

C. Cortisol- after a fast, cortisol is released. This is a lipid- soluble hormone. It will enter the nucleus and activate genes that code for enzymes that build glucose, for example, from amino acids.