PHY6110 Lecture 7 PDF - Cell Signaling

PHY6110 Lecture 7 CELL SIGNALING Cell signaling Cellular signaling is the process by which cells receive and respond to signals from their environment and other cells. It's a fundamental property of all cells, and is essential for cells to grow and function normally. Cellular signaling involves th...

PHY6110 Lecture 7 CELL SIGNALING Cell signaling Cellular signaling is the process by which cells receive and respond to signals from their environment and other cells. It's a fundamental property of all cells, and is essential for cells to grow and function normally. Cellular signaling involves the following steps: Signal A chemical substance, such as a hormone, neurotransmitter, or growth factor, binds to a receptor on the ce Reception The binding triggers a chain of events that carries the signal into the cell. Response The cell responds to the signal, which can be a specific action like cell division or cell death. Cell signaling is important for many processes, including: Development: During embryonic development, cell signaling regulates the interactions between different t Immune response: When the body recognizes pathogens, cell signaling initiates an immune response. Homeostasis: Cell signaling helps maintain homeostasis in all organisms. If signaling between or within cells is disrupted, it can lead to inappropriate cellular responses and diseases Cells typically communicate using chemical signals. These chemical signals, which are proteins or other molecules produced by a sending cell, are often secreted from the cell and released into the extracellular space. There, they can float – like messages in a bottle – over to neighboring cells. Not all cells can “hear” a particular chemical message. In order to detect a signal (that is, to be a target cell), a neighbor cell must have the right receptor for that signal. When a signaling molecule binds to its receptor, it alters the shape or activity of the receptor, triggering a change inside of the cell. Signaling molecules are often called ligands, a general term for molecules that bind specifically to other molecules (such as receptors). The message carried by a ligand is often relayed through a chain of chemical messengers inside the cell. Ultimately, it leads to a change in the cell, such as alteration in the activity of a gene or even the induction of a whole process, such as cell division. Thus, the original intercellular (between-cells) signal is converted into an intracellular (within- cell) signal that triggers a response. Receptors and ligands come in many forms, but they all have one thing in common: they come in closely matched pairs, with a receptor recognizing just one (or a few) specific ligands, and a ligand binding to just one (or a few) target receptors. Binding of a ligand to a receptor changes its shape or activity, allowing it to transmit a signal or directly produce a change inside of the cell Types of Receptors Receptors come in many types, but they can be divided into two categories: intracellular receptors, which are found inside of the cell (in the cytoplasm or nucleus), and cell surface receptors, which are found in the plasma membrane. Intracellular receptors Intracellular receptors are receptor proteins found on the inside of the cell, typically in the cytoplasm or nucleus. In most cases, the ligands of intracellular receptors are small, hydrophobic (water-hating) molecules, since they must be able to cross the plasma membrane in order to reach their receptors. For example, the primary receptors for hydrophobic steroid hormones, such as the sex hormones estradiol (an estrogen) and testosterone, are intracellular. Many signaling pathways, involving both intracellular and cell surface receptors, cause changes in the transcription of genes. However, intracellular receptors are unique because they cause these changes very directly, binding to the DNA and altering transcription themselves. When a hormone enters a cell and binds to its receptor, it causes the receptor to change shape, allowing the receptor-hormone complex to enter the nucleus (if it wasn’t there already) and regulate gene activity. Hormone binding exposes regions of the receptor that have DNA-binding activity, meaning they can attach to specific sequences of DNA. These sequences are found next to certain genes in the DNA of the cell, and when the receptor binds next to these genes, it alters their level of transcription. Cell-surface Receptors Cell-surface receptors are membrane-anchored proteins that bind to ligands on the outside surface of the cell. In this type of signaling, the ligand does not need to cross the plasma membrane. So, many different kinds of molecules (including large, hydrophilic or "water-loving" ones) may act as ligands. There are many kinds of cell-surface receptors, but here we’ll look at three common types: ligand-gated ion channels, G protein-coupled receptors, and receptor tyrosine kinases. A typical cell-surface receptor has three different domains, or protein regions: a extracellular ("outside of cell") ligand- binding domain, a hydrophobic domain extending through the membrane, and an intracellular ("inside of cell") domain, which often transmits a signal. The size and structure of these regions can vary a lot depending on the type of receptor, and the hydrophobic region may consist of multiple stretches of amino acids that criss-cross the membrane. Ligand-gated ion channels are ion channels that can open in response to the binding of a ligand. To form a channel, this type of cell-surface receptor has a membrane-spanning region with a hydrophilic (water- loving) channel through the middle of it. The channel lets ions to cross the membrane without having to touch the hydrophobic core of the phospholipid bilayer. When a ligand binds to the extracellular region of the channel, the protein’s structure changes in such a way that ions of a particular type, can pass through. In some cases, the reverse is actually true: the channel is usually open, and ligand binding causes it to close. Changes in ion levels inside the cell can change the activity of other molecules, such as ion-binding enzymes and voltage-sensitive channels, to produce a response. Neurons, or nerve cells, have ligand-gated channels that are bound by neurotransmitters. G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that share a common structure and method of signaling. The members of the GPCR family all have seven different protein segments that cross the membrane, and they transmit signals inside the cell through a type of protein called a G protein (more details below). GPCRs are diverse and bind many different types of ligands. One particularly interesting class of GPCRs is the odorant (scent) receptors. There are about 800 of them in humans, and each binds its own “scent molecule” – such as a particular chemical in perfume, or a certain compound released by rotting fish – and causes a signal to be sent to the brain, making us smell a smell! When its ligand is not present, a G protein-coupled receptor waits at the plasma membrane in an inactive state. For at least some types of GPCRs, the inactive receptor is already docked to its signaling target, a G protein Receptor tyrosine kinases Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor actually is an enzyme that can catalyze a reaction. Other enzyme-linked receptors have an intracellular domain that interacts with an enzyme Receptor tyrosine kinases (RTKs) are a class of enzyme- linked receptors found in humans and many other species. A kinase is just a name for an enzyme that transfers phosphate groups to a protein or other target, and a receptor tyrosine kinase transfers phosphate groups specifically to the amino acid tyrosine. Small, hydrophobic ligands can pass through the plasma membrane and bind to intracellular receptors in the nucleus or cytoplasm. In the human body, some of the most important ligands of this type are the steroid hormones. Familiar steroid hormones include the female sex hormone estradiol, which is a type of estrogen, and the male sex hormone testosterone. Vitamin D, a molecule synthesized in the skin using energy from light, is another example of a steroid hormone. Because they are hydrophobic, these hormones don’t have trouble crossing the plasma membrane, but they must bind to carrier proteins in order to travel through the (watery) bloodstream. Nitric oxide (NO) is a gas that acts as a ligand. Like Water-soluble ligands are polar or charged and steroid hormones, it can diffuse directly across the plasma membrane thanks to its small size. One of cannot readily cross the plasma membrane. So, its key roles is to activate a signaling pathway in most water-soluble ligands bind to the the smooth muscle surrounding blood vessels, one extracellular domains of cell-surface receptors, that makes the muscle relax and allows the blood vessels to expand (dilate). In fact, the drug staying on the outer surface of the cell. nitroglycerin treats heart disease by triggering the release of NO, dilating vessels to restore blood flow to the heart. Peptide (protein) ligands make up the largest and most diverse class of water-soluble ligands. For instance, growth factors, hormones such as insulin, and certain neurotransmitters fall into this category. Peptide ligands can range from just a few amino acids long, as in the pain-suppressing enkephalins, to a hundred or more amino acids in length Cell-cell signaling involves the transmission of a signal from a sending cell to a receiving cell. However, not all sending and receiving cells are next-door neighbors, nor do all cell pairs exchange signals in the same way. There are four basic categories of chemical signaling found in multicellular organisms: paracrine signaling, autocrine signaling, endocrine signaling, and signaling by direct contact. The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. Paracrine Often, cells that are near one another communicate through the release of chemical messengers (ligands that can diffuse through the space between the cells). This type of signaling, in which cells communicate over relatively short distances, is known as paracrine signaling. Paracrine signaling allows cells to locally coordinate activities with their neighbors. Although they're used in many different tissues and contexts, paracrine signals are especially important during development, when they allow one group of cells to tell a neighboring group of cells what cellular identity to take on. Paracrine The developing spinal cord of an embryo contains a hollow tube of cells that runs along the embryo’s back, called the notochord, and a column of cells that runs parallel to the notochord, called the floor plate. Together, the notochord and floor plate release a signaling molecule called Sonic hedgehog (Shh). As Shh diffuses away from the notochord and floor plate, it forms a gradient, with high levels near the source and low levels further away. The different concentrations of Shh at different points along the gradient help tell nearby cells what types of neurons they should become Cells that are close to the notochord and floor plate receive a high dose of signal and become a specific type of connector neuron (interneuron). Cells that are a little further away get a lower dose of signal and become motor neurons (neurons that connect up to muscles). Cell that are even more distant from the notochord and floor plate receive progressively lower doses of signal and become other types of interneurons. Different levels of Shh signal trigger different responses in cells, causing them to take on distinct identities and characteristics. Signals like Shh, which form gradients and produce different developmental effects depending on the dose of signal, are known as morphogens. Paracrine Autocrine intracellular in autocrine signaling, a cell signals to itself, releasing a ligand that binds to receptors on its own surface (or, depending on the type of signal, to receptors inside of the cell). This may seem like an odd thing for a cell to do, but autocrine signaling plays an important role in many processes. For instance, autocrine signaling is important during development, helping cells take on and reinforce their correct identities. From a medical standpoint, autocrine signaling is important in cancer and is thought to play a key role in metastasis (the spread of cancer from its original site to other parts of the body). In many cases, a signal may have both autocrine and paracrine effects, binding to the sending cell as well as other similar cells in the area. Endocrine When cells need to transmit signals over long distances, they often use the circulatory system as a distribution network for the messages they send. In long-distance endocrine signaling, signals are produced by specialized cells and released into the bloodstream, which carries them to target cells in distant parts of the body. Signals that are produced in one part of the body and travel through the circulation to reach far-away targets are known as hormones. In humans, endocrine glands that release hormones include the thyroid, the hypothalamus, and the pituitary, as well as the gonads (testes and ovaries) and the pancreas. Each endocrine gland releases one or more types of hormones, many of which are master regulators of development and physiology. Endocrine The pituitary releases growth hormone (GH), which promotes growth, particularly of the skeleton and cartilage. Like most hormones, GH affects many different types of cells throughout the body. However, cartilage cells provide one example of how GH functions: it binds to receptors on the surface of these cells and encourages them to divide Cell to Cell Signaling Gap junctions in animals and plasmodesmata in plants are tiny channels that directly connect neighboring cells. These water-filled channels allow small signaling molecules, called intracellular mediators, to diffuse between the two cells. Small molecules and ions are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels without special assistance. Cell to cell The transfer of signaling molecules transmits the current state of one cell to its neighbor. This allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, there are plasmodesmata between almost all cells, making the entire plant into one giant network. In another form of direct signaling, two cells may bind to one another because they carry complementary proteins on their surfaces. When the proteins bind to one another, this interaction changes the shape of one or both proteins, transmitting a signal. This kind of signaling is especially important in the immune system, where immune cells use cell-surface markers to recognize “self” cells (the body's own cells) and cells infected by pathogens