modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). the function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. many lics are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. lics are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and atp-gated channels. g protein–coupled receptors a g protein-coupled receptor within the plasma membrane. g protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. coupling with g proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. ligands can bind either to extracellular n-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (rhodopsin-like family). they are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. g protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, and animals. the ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. g protein-coupled receptors are involved in many diseases. there are two principal signal transduction pathways involving the g protein-coupled receptors: camp signal pathway and phosphatidylinositol signal pathway. when a ligand binds to the gpcr it causes a conformational change in the gpcr, which allows it to act as a guanine nucleotide exchange factor (gef). the gpcr can then activate an associated g protein by exchanging the gdp bound to the g protein for a gtp. the g protein's α subunit, together with the bound gtp, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (gαs, gαi/o, gαq/11, gα12/13).: 1160 g protein-coupled receptors are an important drug target and approximately 34% of all food and drug administration (fda) approved drugs target 108 members of this family. the global sales volume for these drugs is estimated to be 180 billion us dollars as of 2018. it is estimated that gpcrs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. the long ago discovered association between gpcrs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research. enzyme-linked receptors vegf receptors are a type of enzyme-coupled receptors, specifically tyrosine kinase receptors enzyme-linked receptors (or catalytic receptors) are transmembrane receptors that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions. they have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function; and a single transmembrane helix. the signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell. examples of the enzymatic activity include: receptor tyrosine kinase, as in fibroblast growth factor receptor. most enzyme-linked receptors are of this type. serine/threonine-specific protein kinase, as in bone morphogenetic protein guanylate cyclase, as in atrial natriuretic factor receptor intracellular receptors main articles: nuclear receptor and dna-binding domain steroid hormone receptor steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. they are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. the best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (nr3) that include receptors for estrogen (group nr3a) and 3-ketosteroids (group nr3c). in addition to nuclear receptors, several g protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones. signal transduction pathways when binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). the molecules that compose these pathways are known as relay molecules. the multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. the amplifying of a signal is one of the benefits to this multiple step sequence. other benefits include more opportunities for regulation than simpler systems do and the fine-tuning of the response, in both unicellular and multicellular organism. in some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. for example, the neurotransmitter gaba can activate a cell surface receptor that is part of an ion channel. gaba binding to a gabaa receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. gabaa receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. however, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. the activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. the entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway. key components of a signal transduction pathway (mapk/erk pathway shown) a more complex signal transduction pathway is the mapk/erk pathway, which involves changes of protein–protein interactions inside the cell, induced by an external signal. many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. this phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. in this case, the ligand (called epidermal growth factor, or egf) binds to the receptor (called egfr). this activates the receptor to phosphorylate itself. the phosphorylated receptor binds to an adaptor protein (grb2), which couples the signal to further downstream signaling processes. for example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (mapk) pathway. the signal transduction component labeled as "mapk" in the pathway was originally called "erk," so the pathway is called the mapk/erk pathway. the mapk protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor myc and, thus, alter gene transcription and, ultimately, cell cycle progression. many cellular proteins are activated downstream of the growth factor receptors (such as egfr) that initiate this signal transduction pathway. some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. for instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present. complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways. a specific cellular response is the result of the transduced signal in the final stage of cell signaling. this response can essentially be any cellular activity that is present in a body. it can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. these three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. at the end, the end of a signal pathway leads to the regulation of a cellular activity. this response can take place in the nucleus or in the cytoplasm of the cell. a majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus. in unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. in quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. in this context, the signaling molecules are called autoinducers. this signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. bacteria also use contact-dependent signaling, notably to limit their growth. signaling molecules used by multicellular organisms are often called pheromones. they can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction. short-term cellular responses brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responses receptor family example of ligands/ activators (bracket: receptor for it) example of effectors further downstream effects ligand gated ion channels acetylcholine (such as nicotinic acetylcholine receptor), changes in membrane permeability change in membrane potential seven helix receptor light(rhodopsin), dopamine (dopamine receptor), gaba (gaba receptor), prostaglandin (prostaglandin receptor) etc. trimeric g protein adenylate cyclase, cgmp phosphodiesterase, g-protein gated ion channel, etc. two component diverse activators histidine kinase response regulator - flagellar movement, gene expression membrane guanylyl cyclase atrial natriuretic peptide, sea urchin egg peptide etc. cgmp regulation of kinases and channels- diverse actions cytoplasmic guanylyl cyclase nitric oxide(nitric oxide receptor) cgmp regulation of cgmp gated channels, kinases integrins fibronectins, other extracellular matrix proteins nonreceptor tyrosine kinase diverse response . regulating gene activity signal transduction pathways that lead to a cellular response brief overview of some signaling pathways (based on receptor families) that control gene activity frizzled (special type of 7helix receptor) wnt dishevelled, axin - apc, gsk3-beta - beta catenin gene expression two component diverse activators histidine kinase response regulator - flagellar movement, gene expression receptor tyrosine kinase insulin (insulin receptor), egf (egf receptor), fgf-alpha, fgf-beta, etc (fgf-receptors) ras, map-kinases, plc, pi3-kinase gene expression change cytokine receptors erythropoietin, growth hormone (growth hormone receptor), ifn-gamma (ifn-gamma receptor) etc jak kinase stat transcription factor - gene expression tyrosine kinase linked- receptors mhc-peptide complex - tcr, antigens - bcr cytoplasmic tyrosine kinase gene expression receptor serine/threonine kinase activin(activin receptor), inhibin, bone-morphogenetic protein(bmp receptor), tgf-beta smad transcription factors control of gene expression sphingomyelinase linked receptors il-1(il-1 receptor), tnf (tnf-receptors) ceramide activated kinases gene expression cytoplasmic steroid receptors steroid hormones, thyroid hormones, retinoic acid etc work as/ interact with transcription factors gene expression . notch signaling pathway notch-mediated juxtacrine signal between adjacent cells. notch is a cell surface protein that functions as a receptor. animals have a small set of genes that code for signaling proteins that interact specifically with notch receptors and stimulate a response in cells that express notch on their surface. molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. ligand receptor interactions such as that of the notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication. notch acts as a receptor for ligands that are expressed on adjacent cells. while some receptors are cell-surface proteins, others are found inside cells. for example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. as part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries. in the case of notch-mediated signaling, the signal transduction mechanism can be relatively simple. as shown in figure 2, the activation of notch can cause the notch protein to be altered by a protease. part of the notch protein is released from the cell surface membrane and takes part in gene regulation. cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. emerging methods