Vasopressin is a neurotransmitter – a signalling molecule of the brain – and it transmits signals by attaching to its receptor V1aR, like a key fitting into a lock. Alter the balance of these molecules and you can change the voles’ behaviour. For example, give extra vasopressin to a prairie vole and it will develop a stronger bond with its partner, but block the receptor and you break the bond.
Cell shrinkage: cells become smaller and lose cell-cell contacts 2. Chromatin condensation: chromatin initially condenses to the periphery of the nucleus and ultimately nuclear fragmentation occurs. During these events DNA is digested in specific ways leading to what is called "laddering" in DNA gels. 3. Cell membrane blebbing (small bulges on cell surface) occurs 4. Cell fragmentation ("apoptotic bodies" are formed) and phagocytosis of these by macrophages.
Alternatively, surface receptors can be activated by specific ligands that bind to "death receptors" (i.e., "Extrinsic Pathway"). Death receptors are members of the tumour necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily. They make up a subfamily characterized by the intracellular death domain (DD). The extrinsic pathway is typically mediated by immune cells, to initiate intracellular signaling and the downstream activation of relevant caspases. Some work suggests both Intrinsic and Extrinsic Pathways mediate the apoptosis during oogenesis and likely of aging eggs after fertilization. The binding of TNF-α to its receptor (TNF-receptor or TNFR) makes the receptors intracellular death domain available for binding to TRADD (TNFR-associated death domain). TRADD is an adaptor that in turn directs the binding of FADD (Fas-associated death domain) another adaptor that mediates the binding of pro-caspase-8 to this multiprotein complex. This leads to the proteolytic processing of the inactive pro-caspase-8 into the active caspase-8 enzyme. Caspase-8 is an initiator caspase that in turn proteolytically activates several other caspases. The activated caspases-3,6 and 7 are effectorcaspases that proteolytically digest a number of target proteins ultimately leading to apoptosis. There are a number of other apoptosis-specific pathways each of which involves unique sets of adaptor proteins and caspases and each of which is designed to direct apoptosis at a specific place or time in human development or other aspects of cell function.
Dept. of Natural SciencesUniversity of St. La Salle Bacolod City
CELL SIGNALING SYSTEM Cell communication begins when a receptor protein on the target cell receives an incoming extracellular signal and converts it to the intracellular signals that direct cell behavior. Signal reception and signal transduction are the events referred to in cell signaling.
COMPONENTS OF A SIGNALING SYSTEM1. LIGAND - a molecule that binds to a specific site on another molecule, usually a protein receptor; provides a signal or an external message to the cell; also known as primary messenger Peptides / Proteins- growth Factors Amino acid derivatives - epinephrine, histamine Other small biomolecules - ATP Steroids, prostaglandins Gases - Nitric Oxide (NO) Photons Damaged DNA Odorants, tastants2. RECEPTOR- typically an extracellular ligand- binding molecule; a few are cytoplasmic forms
When a ligand bindsto a receptor protein,this activates a signaltransduction pathway that is mediated by aseries of intracellular signaling proteins. These interact with target proteins, altering them tochange cell behavior. The repertoire of changes a cell can show depends on which receptors it possess, how these are coupled to signal transduction pathways, and how these are coupled to gene regulation.
A ligand binds its receptor through a In situations number of specific weak non-covalent where even low bonds by fitting into a specific binding concentrations site or "pocket". of a ligand will result in binding of most of the cognate receptors, the receptor affinity is considered to be high (Ka). Low receptor affinity occurs when a high concentration of the ligand is required for most receptors to be occupied.
With prolonged exposure to a ligand (and occupation of the receptor) cells often become desensitized. Desensitization of the cell to a ligand depends upon receptor down-regulation by either: o removal of the receptor from the cell surface (receptor-mediated endocytosis) or, o alterations to the receptor that lower the affinity for ligand or that render it unable to initiate the changes in cellular function (such as phosphorylation). Desensitization may lead to tolerance, a phenomenon that results in the loss of medicinal effectiveness of some medicines that are over prescribed. Receptor binding activates a "preprogrammed" sequence of signal transduction events that may require immediate responses; others maybe slow.
Changes in cell May movement, involve secretion, or genes metabolism (e.g., (i.e., rapid increasedphosphorylation cell growth of target and proteins) division
Every cell type displays Cell responses to signals may vary a set of receptor proteins that enables itto respond to a specific set of signal moleculesproduced by other cells.These signal moleculeswork in combinations toregulate the behavior of the cell. Cells mayrequire multiple signals(blue arrows) to survive, additional signals (red arrows) to divide, andstill other signals (greenarrows) to differentiate. If deprived of survival signals, most cells undergo a form of cell suicide known asprogrammed cell death, or apoptosis.
Cells use different strategies for sending signalsA.Hormones produced in endocrine glands are secreted into the bloodstream and are often distributed widely throughout the body.B.Paracrine signals are released by cells into the extracellular medium in their neighborhood and act locally.
C. Neuronal signals or neurotransmitters are transmitted along axons to remote target cells.D. Cells that maintain an intimate membrane-to-membrane interface can engage in contact dependent ( juxtacrine) signaling. Many of the same types of signal molecules are used for endocrine, paracrine, and neuronal signaling. The crucial differences lie in the speed and selectivity with which the signals are delivered to their targets.
Contact-dependent signaling controls nerve-cell production.The signals that control the process of nerve cell specializationfrom an embryonic epithelial sheet are transmitted via direct cell–cell contacts: each future neuron delivers an inhibitory signal tothe cells next to it, deterring them from specializing as neuronstoo. Both the signal molecule (Delta)and the receptor molecule (Notch) aretransmembrane proteins. In mutantswhere the mechanismfails, some celltypes (such asneurons)are producedin greatexcessat theexpenseof others.
CELL SIGNALING CASCADES They transform, or transduce, the signal into a molecular form suitable for passing the signal along or stimulating a response. They relay the signal from the point in the cell at which it is received to the point at which the response is produced. In many cases, signaling cascades also amplify the signal received, making it stronger, so that a few extracellular signal molecules are enough to evoke a large intracellular response. The signaling cascades can also distribute the signal so as to influence several processes in parallel: at any step in the pathway, the signal can diverge and be relayed to a number of different intracellular targets, creating branches in the information flow diagram and evoking a complex response. Each step in this signaling cascade is open to modulation by other factors, including other external signals, so that the effects of http://highered.mcgraw- the signal can be tailored to the conditions hill.com/sites/0072437316/student_view0 prevailing inside or outside the cell. /chapter7/animations.html#
There are different ways in which signals maybe integrated:
Intracellular signaling proteins act as molecular switches. Intracellular signaling proteins can be activated by the addition of a phosphate group and inactivated by the removal of the phosphate. In some cases, the phosphate is added covalently to the protein by a protein kinasethat transfers the terminal phosphate group from ATP to the signaling protein;the phosphate is then removed by a protein phosphatase (A). In other cases, a GTP-binding signaling protein is induced to exchange its bound GDP for GTP; hydrolysis of the bound GTP to GDP then switches the protein off (B).
Some intracellularsignaling proteinsserve to integrate incoming signals. Signals A and B may activate different cascades of proteinphosphorylations, each of which leads to the phosphorylation of proteinY but at different sites on the protein (A). Protein Y is activated only when both of these sites are phosphorylated, and therefore it is active onlywhen signals A and B are simultaneously present. Alternatively, signals A and B could lead to the phosphorylation of two proteins, X and Z, which then bind to each other to create the active protein XZ (B).
NEUROTRANSMITTERS Acetylcholine can induce different responses in different target cells. Different cell types are configured to respond to acetylcholine in different ways. Acetylcholine binds to similar receptor proteins on heart muscle cells (A) and salivary gland cells (B), but it evokes different responses in each cell type. Skeletal muscle cells (C) produce a different type of receptorprotein for the same signal. The different receptor types generatedifferent intracellular signals, thus enabling the different types of muscle cells to react differently to acetylcholine. (D) For such a versatile molecule, acetylcholine has a fairly simple structure.
HORMONES Chemical signals known as hormones are secreted by one tissue to regulate another tissue, often over a distance. Hormones are often transmitted by the circulatory system. Hormones control many physiological functions including growth and development, rates of physiological processes, concentrations of sugars and minerals, and responses to stress. Hormones can be amino acid derivatives (epinephrine), peptides (antidiuretic hormone, vasopressin), proteins (insulin), or lipid-like hormones including steroids (testosterone)
Hormonal signals can be classified by the distancethat they travel to reach their target cells.1.An endocrine hormone travels through the circulatory system and a paracrine hormone acts only upon near by cells. A paracrine hormone is roughly equal to a growth factor.2.Endocrine tissues secrete directly into the blood- stream and exocrine tissues into ducts for transport of the secretions to other parts of the body. o The pancreas has both endocrine (insulin and glucagon) and paracrine (digestive enzymes) functions. o Once in the circulatory system, the endocrine hormones will eventually reach their target tissue(s) such as heart and liver (epinephrine) or liver and skeletal muscles (insulin).
The steroid hormonecortisol acts by activatinga gene regulatory protein. Cortisol diffuses directly across the plasma membrane and binds toits receptor protein, which is located in the cytosol. The hormone–receptor complex is then transported into the nucleus via the nuclear pores. Cortisol binding activates the receptorprotein, which is then able to bind to specific regulatory sequences in the DNA and activate gene transcription. The receptors for cortisol and some other steroid hormones are located in the cytosol; those for the other signal molecules of this family are already bound to DNA in the nucleus.
GROWTH FACTORS Growth factors act as primary messengers. In addition to nutrients, cell often need growth factors to grow including: Platelet-derived growth factor (PDGF), Insulin, insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), epidermal growth factor (EGF), nerve growth factor (NGF) These RTK ligands function in much more than growth and cell division.
Disruption of growth factor signaling through RTKs can have dramatic effects on embryonic development. The fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) function in both embryonic and adult signaling. FGFRs are important in the development of mesoderm, the embryonic tissue that eventually becomes muscle, cartilage, bone and blood cells. A mutantreceptor that, due to dimerization with normal versions of FGFR, has a dominant inhibitory effect upon the normal activity is a dominant negative mutation.
A dominant negativemutant version of FGFRmRNA injected into frogeggs cause the failure of mesodermal tissue to develop and producestadpoles with heads but no bodies. In humans,defects in FGFRs lead tothanatophoric dysplasia severe bone abnormalities (fatal in infancy) and achondroplasia (dwarfism).
CALCIUM AS A SIGNAL Ca+2 ions act to regulate many cellular functions. The release of Ca+2 ions is a key event in many signaling processes. Intracellular concentrations can be followed by injection of Ca+2 indicator fluorescent dyes, presence of ligand or increase in IP3 and monitoring the increase in fluorescence. Ca+2 levels in the cytoplasm is normally kept low (10-4) by Ca+2 The Ca+2 ionophore pumps in the plasma membrane (out of the cell) and by sodium- releases Ca+2 from calcium exchangers: a) out of the cell, b) into ER lumen and c) the intracellular into the mitochondrion. stores that mimics Ca+2 stores can be released from the ER by the IP3 receptor effect of IP3 channel and ryanodine receptor channel which opens in the activation. presence of Ca+2 itself (Ca+2 -induced Ca+2 release).
Although other proteins bind Ca+2 to controlWhen Ca+2 ions are activity, most often binding to the protein present, two bind calmodulin, forming a Ca+2-calmodulin each globular end complex is an intermediate step. (4 in total); the helical arm region then changes conformation (theactive complex) and then wraps around the calmodulin- binding site of target protein kinases and phosphatases which may varydepending upon thetarget cell (different cells have different responses).
Fertilization of animal eggs reveals an important example of calcium-mediated signal transduction after a receptor-ligand interaction. Initially the sperm binds the egg’s surface at the membrane and within 30 seconds, a wave of calcium release spreads from the site of sperm contact.Two main events in fertilization rely on calcium release: Calcium stimulates the fusion of the cortical granules with the egg’s plasma membrane to alter the coat surrounding the egg to help prevent the binding of another sperm cell to the egg (slow block to polyspermy). Calcium initiates egg activation, the resumption of metabolic processes.
The conversion of glucose into pyruvate is thus accelerated, resulting in an increase in the concentration of ATP in the cytosol (2). The binding of ATP to ATP-sensitive K channels closes these channels (3), thus reducing the efflux of K ions from the cell. The resulting small depolarization of the plasma membrane (4) triggers the opening of voltage-sensitive Ca+2 channels (5). The influx of Ca+2 ions raises the Secretion of insulin from pancreatic cells in cytosolic Ca+2 concentration, triggeringresponse to a rise in blood glucose. The entry of the fusion of insulin- glucose into cells is mediated by the GLUT2 containing secretory glucose transporter (1). A rise in extracellular vesicles with the plasma glucose from 5 mM, (fasting state), causes a membrane and theproportionate increase in the rate of glucose entry. secretion of insulin (6).
NITRIC OXIDE AS A SIGNAL Nitric oxide (NO) is a toxic, short-lived gas molecule and has been found to be a signaling molecule in the cardiovascular system. The binding of acetylcholine causes the release of NO in vascular endothelial cells. NO may couple the G protein-linked receptor stimulation in endothelial cells to relaxation of smooth muscle cells in blood vessels. Note that NO gas is highly toxic when inhaled and should not be confused with nitrous oxide (N2O), also known as laughing gas.
Regulation of contractility of arterial smooth muscle by nitric oxide (NO) and cGMP. Upon activation by acetylcholine, NO diffuses from the endothelium and activates an intracellular NO receptor with guanylyl cyclase activity in nearby smooth muscle cells.The resulting rise in cGMP leads to activation of protein kinase G (PKG), relaxation of themuscle, and thus vasodilation. The cell-surface receptor for atrial natriuretic factor (ANF)also has intrinsic guanylyl cyclase activity. Stimulation of this receptor on smooth muscle cells also leads to increased cGMP and subsequent muscle relaxation.
Odorants (scentchemicals) activate Gsand adenylate cyclase in scent-sensitivenerve cells. cAMP thenopens a non-selective cation channel in the plasma membrane.
CELL SIGNALING AND APOPTOSIS Cells regulate programmed cell death (PCD) or apoptosis which is a very ordered mechanism to prune away unneeded structures, control the number of cells in particular tissues, and sculpt complex organs. It is an important part of normal development (removal of webbing of fingers and toes in embryos, extra neurons in infants and old blood cells in adults). There is some evidence that activation of the apoptosis pathway in adult neurons is responsible for Alzheimer’s disease and CV stroke. The cell death program involves the activation specific proteases known as caspases and procaspases. The Fas ligand on the surface of lymphocytes bind the Fas receptors on the infected cell’s surface. This results in the clustering of Fas, the attachment of adaptor proteins and assembly of the procaspases at this site. The procaspases activate each other to start a cascade of events that ends in apoptosis.