Signal Transduction and Receptor types PDF - COCP-KFU Lecture Notes

Signal Transduction and Receptor types PG Lecture Series COCP-KFU ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Intending Learning Outcomes Define and describe signal...

Signal Transduction and Receptor types PG Lecture Series COCP-KFU ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Intending Learning Outcomes Define and describe signal transduction Describe types of signalling associated with ligand/drug action Compare internal receptors with cell-surface receptors Describe types of drug receptors and their function. Understand the differences in their actions. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signal Transduction The binding of a drug to the receptor (extracellularly), acts as a “signal” for the subsequent event or events (intracellularly) that eventually leads to the pharmacological response. This transmission of the signal is called signal transduction However, the intracellular chain of events that are involved in this process is called signal transduction cascades ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signal Transduction A number of intracellular molecules can be involved in those chain of events. The function of the cascades is to amplify the signal of the drug. These signal transduction cascades, also called intracellular signalling pathways and hence producing multiple intracellular signals for every one receptor that is bound. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signal Transduction Activation of receptors can trigger the synthesis of small molecules called second messengers, which initiate and coordinate intracellular signalling pathways. For example, cyclic AMP (cAMP) is a common second messenger involved in signal transduction cascades. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signal Transduction cAMP is synthesized from ATP by the enzyme adenylyl cyclase, which resides in the cell membrane. The activation of adenylyl cyclase can result in the manufacture of hundreds or even thousands of cAMP molecules. These cAMP molecules activate the enzyme protein kinase A (PKA), which then phosphorylates multiple protein substrates by attaching phosphate groups to them. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signal Transduction Each step in the cascade further amplifies the initial signal, and the phosphorylation reactions mediate both short- and long-term responses in the cell. The action of cAMP is terminated by the degradation of the enzyme phosphodiesterase. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signal Transduction Another examples of second messengers include: Diacylglycerol (DAG) Inositol 1,4,5-triphosphate (IP3). Both are produced by the enzyme phospholipase, also a membrane protein. IP3 causes the release of Ca2+ — yet another second messenger — from intracellular stores. Together, DAG and Ca2+ activate another enzyme called protein kinase C (PKC). ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Signaling molecules Classes of signaling College of Clinical Pharmacy King Faisal University molecules Hydrophobic signaling molecules Use nuclear receptors Neurotransmitters Peptide signaling molecuels Eicosanoids ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Hydrophobic signaling molecules Passively diffuse across cell membrane Examples: Steroid hormones, Vitamin D3 Thyroid hormone, Retinoid acid, Nitric oxide and CO All use intracellular receptors and function as activators or repressors of genes ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Neurotransmitters They carry signals between neurons, from neurons to other target cells Hydrophilic, can’t cross the plasma membrane of target cells, hence, they bind to cell surface receptors Type of receptors include Ligand-gated ion channels Neurotranmitter binding opens the channels ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Peptide signaling molecules Example: Peptide hormones, Neuropeptides, polypeptide growth factors, Short polypeptides, They have a variety of functions All use cell membrane anchored receptors ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Eicosanoids Eicosanoids are lipid signaling molecules which include prostaglandins, prostacyclin, thromboxanes, and leukotrienes Arachindonic derived from phospholipids, by phospholypase A2 ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of Signal Transduction There are four categories of chemical signaling transduction. 1.Pracrine signaling 2.Endocrine signaling 3.Autocrine signaling 4.Direct signaling across gap junctions ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of Signal Transduction The main difference between the different categories of signaling is the distance that the signal travels to reach the target cell Not all cells are affected by the same signals ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of Signal Transduction In chemical signaling, a cell may target itself (autocrine signaling) OR, a cell connected by gap junctions, a nearby cell (paracrine signaling) OR a distant cell (endocrine signaling) OR Direct signalling ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Paracrine signaling In paracrine signaling, a molecule released by one cell acts on neighboring target cells Paracrine signals move by diffusion through the extracellular matrix These types of signals usually elicit quick responses that last only a short amount of time In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Paracrine signaling An example is provided by the action of neurotransmitters in carrying signals between nerve cells at a synapse The small distance between nerve cells allows the signal to travel quickly; this enables an immediate response, such as, Take your hand off the stove! ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Endocrine Signaling Signals from distant cells are called endocrine signals, and they originate from endocrine cells These types of signals usually produce a slower response but have a longer-lasting effect The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy Endocrine Signaling King Faisal University Hormones travel the large distances between endocrine cells and their target cells via the bloodstream Because of their form of transport, hormones get diluted and are present in low concentrations when they act on their target cells This is different from paracrine signaling, in which local concentrations of ligands can be very high ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Autocrine signals College of Clinical Pharmacy King Faisal University Autocrine signals are produced by signaling cells that can also bind to the ligand that is released This means the signaling cell and the target cell can be the same or a similar cell Autocrine signaling also regulates pain sensation and inflammatory responses Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Direct Signaling Across Gap College of Clinical Pharmacy King Faisal University Junctions Gap junctions are connections between the plasma membranes of neighboring cells These water-filled channels allow small signaling molecules, called intracellular mediators, to diffuse between the two cells Small molecules, such as calcium ions (Ca2+), can move between cells, but large molecules like proteins and DNA cannot fit through the channels. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Direct Signaling College of Clinical Pharmacy King Faisal University The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell This allows a group of cells to coordinate their response to a signal that only one of them may have received ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Signaling by secreted molecules Endocrine signaling—signaling molecules (hormones), target cells at distant body sites Example: estrogen. Paracrine signaling—act on neighboring target cells, e.g., neurotransmitters Autocrine signaling—respond to self signaling molecules T lymphocytes: proliferation in response to cytokines produced by the same cell ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Summary of different signaling College of Clinical Pharmacy King Faisal University molecules Paracrine signaling acts on nearby cells, endocrine signaling uses the circulatory system to transport ligands, and autocrine signaling acts on the signaling cell Signaling via gap junctions involves signaling molecules moving directly between adjacent cells. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of drug receptors Given the diversity of drug molecules, it might seem likely that the interactions between drugs and their molecular targets would be equally diverse Therefore, Receptors can be divided into major categories: A. Transmembrane proteins on the target-cell surface (Cell-surface receptors) B. Intracellular receptors ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University  ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors: Cell-surface receptors College of Clinical Pharmacy King Faisal University Cell-surface receptors spans the plasma membrane and performs signal transduction, through which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell- specific proteins or markers because they are specific to individual cell types. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy Cell-surface receptors King Faisal University Cell-surface receptor proteins are fundamental to normal cell functioning, therefore, a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension, asthma, heart disease, and cancer. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Cell-surface receptors Cell-surface receptors are involved in most of the signalling mechanism. There are three general categories of cell- surface receptors: A. Ion channel-linked receptors B. G-protein-linked receptors C. Transmembrane Receptors Linked to Intracellular Enzymes (enzyme-linked receptors).  ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors: Ion ‫كلية الصيدلة اإلكلينيكية‬ College of Clinical Pharmacy King Faisal University channel-linked receptors Also called gated-ion channels or ionotropic receptors. Found in nerve and muscle cells (electrically excitable). This type of signalling is mediated through neurotransmitters. Ion channels are essentially gateways in cell membranes that selectively allow the passage of particular ions, and that are induced to open or close by a variety of mechanisms.  ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors: Ion ‫كلية الصيدلة اإلكلينيكية‬ College of Clinical Pharmacy King Faisal University channel-linked receptors Two important types are ligand-gated channels and voltage-gated channels. Ligand-gated channels open only when one or more agonist molecules are bound, and are properly classified as receptors, since agonist binding is needed to activate them. Voltage-gated channels are gated by changes in the transmembrane potential rather than by agonist binding  ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors: Ion ‫كلية الصيدلة اإلكلينيكية‬ College of Clinical Pharmacy King Faisal University channel-linked receptors Example of a ligand-gated channel is benzodiazepine tranquillisers. These drugs bind to a region of the GABAA receptor–chloride channel complex that is distinct from the GABA binding site and facilitate the opening of the channel by the inhibitory neurotransmitter GABA ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors-Voltage- College of Clinical Pharmacy King Faisal University gated There are multiple isoforms of voltage-gated channels such as Na+, K+, Ca2+, and Cl– ions. In nerve and muscle cells, voltage-gated Na+ channels are responsible for the generation of robust action potentials that depolarize the membrane from its resting potential of –70 mV up to a potential of +20 mV within a few milliseconds. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors-Voltage- College of Clinical Pharmacy King Faisal University gated The voltage-activated Na+ channels in pain neurons are targets for local anesthetics, such as lidocaine and tetracaine, which block the pore, inhibit depolarization, and thus block the sensation of pain. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors-GPCR College of Clinical Pharmacy King Faisal University GPCR binds a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane. They are a large family of transmembrane receptors that have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors:GPCR College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors-GPCR College of Clinical Pharmacy King Faisal University Amongst the ligands for GPCRs are neurotransmitters such as ACh, biogenic amines such as NE, all eicosanoids and other lipid-signalling molecules, peptide hormones, opioids, amino acids such as GABA, and many other peptide and protein ligands. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy GPCR and disease King Faisal University Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G- protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of drug receptors Intracellular receptors The signal molecule has to be small to diffuse across the plasma membrane and bind to receptor proteins inside the target cell-either in the cytosol or nucleus. 1. Transmembrane enzymes and non-enzymes receptors 2. Nuclear receptors ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors College of Clinical Pharmacy King Faisal University Transmembrane receptors linked to intracellular enzymes are cell-surface receptors with intracellular domains that are associated with an enzyme. Examples: 1. Receptor Tyrosine Kinases A kinase is an enzyme that transfers phosphate groups from ATP to another protein ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of drug receptors Tyrosine kinases include receptors for hormones such as insulin; growth factors such: Epidermal growth factor (EGF), Platelet-derived growth factor (PDGF), Vascular endothelial growth factor (VEGF) and ephrins. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University Types of drug receptors Human epidermal growth factor receptor 2 (HER2) is a protein receptor tyrosine kinase. In 30 percent of human breast cancers, HER2 is permanently activated, resulting in unregulated cell division. Lapatinib, a drug used to treat breast cancer, inhibits HER2 receptor tyrosine kinase auto-phosphorylation (the process by which the receptor adds phosphates onto itself), thus reducing tumor growth by 50 percent. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University  ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors: Nuclear ‫كلية الصيدلة اإلكلينيكية‬ College of Clinical Pharmacy King Faisal University receptors Nuclear receptors are transcription factors that orchestrate complex regulatory networks in many biological processes, including cell proliferation, metabolism, immunity, and development. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University  ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ Types of drug receptors: Nuclear ‫كلية الصيدلة اإلكلينيكية‬ College of Clinical Pharmacy King Faisal University receptors They include receptors for steroid hormones, thyroid hormones, retinoic acid, vitamin D, fatty acids, and cholesterol metabolites. Regulating their gene transcription. ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University ‫كلية الصيدلة اإلكلينيكية‬ ‫ﺟﺎﻣﻌﺔ اﻟﻤﻠﻚ ﻓﯿﺼﻞ‬ College of Clinical Pharmacy King Faisal University