Cell Signaling Types & Molecules PDF

Case 9 - What language do cells speak? 1. What are the different types of cell signals? What type of molecules are used? Overview of cell signaling 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 m...

Case 9 - What language do cells speak? 1. What are the different types of cell signals? What type of molecules are used? Overview of cell signaling 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. Forms of signaling There are four basic categories of chemical signaling found in multicellular organisms: 1. Paracrine signaling 2. Autocrine signaling 3. Endocrine signaling 4. Contact dependent 5. Synaptic signaling Paracrine signaling (indirect) 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. - Molecules Used: Often involves local mediators such as neurotransmitters, prostaglandins, and growth factors. Synaptic signaling (indirect) One unique example of paracrine signaling is synaptic signaling, in which nerve cells transmit signals. This process is named for the synapse, the junction between two nerve cells where signal transmission occurs. When the sending neuron fires, an electrical impulse moves rapidly through the cell, traveling down a long, fiber-like extension called an axon. When the impulse reaches the synapse, it triggers the release of ligands called neurotransmitters, which quickly cross the small gap between the nerve cells. When the neurotransmitters arrive at the receiving cell, they bind to receptors and cause a chemical change inside of the cell (often, opening ion channels and changing the electrical potential across the membrane). The neurotransmitters that are released into the chemical synapse are quickly degraded or taken back up by the sending cell. This "resets" the system so the synapse is prepared to respond quickly to the next signal. - Molecules Used: Primarily neurotransmitters (e.g., dopamine, serotonin, acetylcholine). Autocrine signaling (indirect) 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. - Molecules Used: Typically involves signaling molecules like cytokines or growth factors. Endocrine signaling (indirect) 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. - Molecules Used: Involves hormones (e.g., insulin, estrogen, adrenaline) produced by endocrine glands. Signaling through cell-cell contact (direct) 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. 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. - Molecules Used: Involves membrane-bound signals like ligands and their corresponding receptors on adjacent cells. Which molecules are used? - Hydrophobic - Hydrophilic (neurotransmitters) - Gasses (NO, CO) - Ions (K+, Na+, Ca2+) - Amino acids - Peptides - Proteins - Nucleotides (miRNA) - Steroid hormones - Fatty acid derivatives - Gasses Proteins One secretion mechanism is exocytosis Another way is ‘shaving’. Micro RNA’s Single stranded → if you would release without protection → degradation Protection: - Connect to protein (HDL, RBP) - Packs in vesicle 2. What are the different direct connections/communications? Gap junctions (communication junctions) Gap junctions are channels between neighboring cells that allow for the transport of ions, water, and other substances. In vertebrates, gap junctions develop when a set of six membrane proteins called connexins form an elongated, donut-like structure called a connexon. When the pores of connexons in adjacent animal cells align, a channel forms between the cells. 6 connexins → connexon → 2 connexons → gap junction Gap junctions are particularly important in cardiac muscle: the electrical signal to contract spreads rapidly between heart muscle cells as ions pass through gap junctions, allowing the cells to contract simultaneously. - Really small in size → so small molecules can pass through (1.5 nm diameter) - Ca2+, cyclic AMP, inositol triphosphate, nucleotides, amino acids, small peptides, vitamins - NO molecules > 5 kilo Dalton Gap junction trafficking Gap junctions open/close within seconds By closing gap junctions healthy cells can be protected from damaged neighboring cells - Damaged cells → permeable → high influx of Ca2+ and leaking of valuable metabolites - High Ca2+ influx immediately closes gap junctions → prevent further damage Tight junctions (occluding junctions) Tight junctions create a watertight seal between two adjacent animal cells, helping to create a selective barrier that regulates the passage of molecules between cells. At the site of a tight junction, cells are held tightly against each other by many individual groups of tight junction proteins called claudins, each of which interacts with a partner group on the opposite cell membrane. The groups are arranged into strands that form a branching network, with larger numbers of strands making for a tighter seal. The purpose of tight junctions is to keep liquid from escaping between cells, allowing a layer of cells (for instance, those lining an organ) to act as an impermeable barrier. For example, the tight junctions between the epithelial cells lining your bladder prevent urine from leaking out into the extracellular space.  - Influence/regulate the membrane proteins in the membrane → modify what is transported Anchoring junctions Anchoring junctions are specialized cellular structures that provide mechanical stability by linking the cytoskeleton of one cell to another or to the extracellular matrix. These junctions are crucial in maintaining the structural integrity of tissues, especially those exposed to mechanical stress, such as skin, heart, and muscles. In addition to their role in physical anchoring, they also participate in cell signaling, helping to regulate cell shape, movement, and signaling pathways related to tissue development and repair. There are several types of anchoring junctions, each associated with different components of the cytoskeleton and providing distinct functions: Adherens Junctions Function: Link the actin cytoskeleton of one cell to the actin cytoskeleton of a neighboring cell, playing a key role in maintaining tissue architecture and cell shape. Key Proteins: - Cadherins: Transmembrane proteins that mediate calcium-dependent cell-cell adhesion. - Catenins: Proteins that link cadherins to the actin cytoskeleton. Location: Found in epithelial and endothelial cells, as well as in tissues that require coordinated contraction or movement. Example in tissues: In epithelial cells, adherens junctions form a continuous belt around the cell (often referred to as a "zonula adherens") that helps maintain cell polarity and adhesion. There are also Desmosomes and Hemidesmosomes Desmosomes Function: Provide strong adhesion between adjacent cells, linking the intermediate filaments (such as keratin) of one cell to those of another. Desmosomes are essential for tissue integrity and resistance to mechanical stress. Hemidesmosomes Function: Attach epithelial cells to the underlying basement membrane (extracellular matrix). Hemidesmosomes link intermediate filaments of the cytoskeleton (like keratin) to the extracellular matrix, anchoring cells to the tissue scaffold. Integrins → cell to extracellular matrix adhesion Cadherins → cell-cell adhesion Actin-linked cell matrix junction (focal adhesions) Juxtacrine communication It works with a membrane bound receptor molecule. 3. What are the different types of receptors (membrane ones main focus)? Cellular response on ‘external signals’ Concentration of external signals is very low, usually < 10^-8 M. Affinity of receptors for ligands is high, Ka > 10^8 liters/mole One signal can have different effect on different tissue Acetylcholine → heart muscle cell: decreased rate and force of contraction → skeletal muscle cell: contraction → salivary gland cell: secretion Gasses (NO) → smooth muscle cells: relaxation i Types of receptors Intracellular/nuclear 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. 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. In promoter region, response element → can block or activate transcription The ligands are hormones. - Cholesterol → cortisol, estradiol, testosteron, vitamine D3 - Tyrosine → thyroxine - Vitamin A → retinoic acid From most nuclear receptors the ligand is known, the receptors with unknown ligands are orphan receptors. Transduction: Outside of the cell first messenger Second messenger is inside - Water soluble or lipid soluble → cell membrane Signal is usually amplified → autophosphorylation 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. 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 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, such as Ca2+ or Cl-, 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. - Allows rapid change of ion permeability of the membrane and as such the excitability of a target cell - Rapid signaling between nerve cells and electrically excitable target cells, like muscle and other nerve cells Example: G protein-coupled receptors (GPCRs) When an appropriate ligand binds to the receptor, the receptor undergoes a conformational change, and is transmitted to its cytosolic regions. They activate the G-protein, the protein composed of three subunits, alpha, beta and gamma. The alpha and gamma subunits have covalently attached lipid tails that anchor the protein to the plasma membrane. In the absence of a signal the alpha has a GDP bound, and the protein is inactive. The receptor only binds to the G-protein once the receptor is activated. An activated receptor induces a conformational change in the alpha subunit, causing the GDP to dissociate. GTP can bind in the place of the GDP. GTP binding causes a further change in the G protein, activating both the alpha subunit and beta-gamma complex. In some cases the alpha subunit dissociates from the beta-gamma complex, while in other cases they stay together. Either way both of the activated components can now regulate the activity of target protein in the plasma membrane. The activated protein then relays the signal to other components in the signaling cascade. Eventually the alpha subunit hydrolyses its bound GTP to GDP, which inactivates the subunit. This step is often accelerated by the binding of another protein, RGS. The inactivated GDP bound alpha subunit reforms an inactive G-protein with the beta-gamma complex. Turning off other downstream events. If the ligand stays bound to the receptor it can continue to activate G-proteins. Upon prolonged stimulation the receptors eventually inactivate, even if the ligand stays bound. Then a receptor kinase phosphorylates the cytosolic region. Then an arrestin is bound to the receptor, this inactivates the receptor. Activated GPCRs can do multiple things - Activate second messengers: cAMP & PIP2 (phosphatidyl-inositol-4,5-bisphosphate) - Direct regulation of downstream pathways Cyclic AMP CAMP has many different effects in various cells. CAMP mediates it effects via activation of protein kinase A. PIP2 (phosphatidyl-inositol-4,5-bisphosphate) Enzyme linked receptors Ras and mapk pathways are triggered. Enzyme-linked receptors, also known as catalytic receptors, are a type of cell surface receptor that play a key role in signal transduction. These receptors typically have an extracellular ligand-binding domain and an intracellular domain with enzymatic activity. When a ligand binds to the receptor, the enzyme activity is activated, leading to intracellular signaling. There are five major subclasses of enzyme-linked receptors: 1. Receptor Tyrosine Kinases (RTKs) - Function: These receptors have intrinsic tyrosine kinase activity in their intracellular domain. Upon ligand binding, the receptors dimerize and autophosphorylate on tyrosine residues, which activates downstream signaling pathways. - Examples: Epidermal growth factor receptor (EGFR), Insulin receptor, Vascular endothelial growth factor receptor (VEGFR). - Ligands: Growth factors, insulin. 2. Receptor Serine/Threonine Kinases - Function: These receptors phosphorylate serine or threonine residues on target proteins in response to ligand binding, triggering intracellular signaling. - Examples: Transforming growth factor-beta (TGF-β) receptors. - Ligands: TGF-β, bone morphogenetic proteins (BMPs). 3. Tyrosine Kinase-Associated Receptors - Function: Unlike receptor tyrosine kinases, these receptors do not have intrinsic kinase activity. Instead, they associate with intracellular tyrosine kinases, such as **Janus kinases (JAKs), to mediate phosphorylation upon ligand binding. - Examples: Cytokine receptors, such as the interleukin receptors and erythropoietin receptors. - Ligands: Cytokines, growth hormones. 4. Receptor Guanylyl Cyclases - Function: These receptors have intrinsic guanylyl cyclase activity, which generates cyclic guanosine monophosphate (cGMP) from GTP upon ligand binding. cGMP then acts as a second messenger in various signaling pathways. - Examples: Atrial natriuretic peptide (ANP) receptor. - Ligands: Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP). 5. Receptor Tyrosine Phosphatases - Function: These receptors have intrinsic phosphatase activity that removes phosphate groups from tyrosine residues on target proteins. This typically results in the termination or modulation of signaling pathways. - Examples: CD45, which is important in regulating immune cell function. - Ligands: The specific ligands are less well characterized, but they are involved in immune regulation and cell signaling processes. Histidine kinase Each of these receptor classes plays a critical role in controlling cellular responses to external stimuli, such as growth, differentiation, immune responses, and metabolic regulation. MAPK signaling cascade