PHM 10303 Receptors and Signal Transduction Lecture PDF

10/10/2023 PHM 10303 Receptors and signal transduction AP Dr Azyyati Mohd Suhaimi Faculty of Pharmacy UniSZA Three Stages of Cell Signaling Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three pr...

10/10/2023 PHM 10303 Receptors and signal transduction AP Dr Azyyati Mohd Suhaimi Faculty of Pharmacy UniSZA Three Stages of Cell Signaling Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes: Reception Transduction Response 1  10/10/2023 Reception Reception - A signal molecule binds to a receptor protein, causing it to change shape Receptor - The component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects The central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics) The binding between a signal molecule (ligand) and receptor is highly specific A conformational change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins 2  10/10/2023 Intracellular receptor Ion channels receptors Four main classes of receptor G-protein-coupled Tyrosine kinase-coupled (GPCR) Intracellular receptor for hydrophobic molecules Some receptor proteins are intracellular, found in cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors E.g., steroid hormones, thyroid hormones, mineralocorticoids An activated hormone-receptor complex can act as a transcription factor, turning on specific genes Receptors stimulate or suppress the transcription of genes by binding to specific DNA sequences Usually targeted for cancer drugs e.g. estrogen receptor agonist for breast cancer, androgen receptor agonist for prostate cancer 3  10/10/2023 Intracellular receptor for hydrophobic molecules Mechanism of glucocorticoid action 4  10/10/2023 Receptors in the plasma membrane for hydrophilic molecules Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane There are three main types of membrane receptors: G-protein-coupled receptors (GPCR) Tyrosine kinases receptors Ion channel receptors Ligand-gated ion channels Voltage-gated ion channels G-protein-coupled receptors (GPCR) A G-protein-coupled receptor is a plasma membrane receptor that works with the help of a G protein When an external signaling molecule binds to a GPCR, it causes a conformational change in the GPCR This change then triggers the interaction between the GPCR and a nearby G protein The G-protein (GDP/GTP – α, β, γ, subunit) acts as an on/off switch 5  10/10/2023 Activation of a single G protein can affect the production of hundreds or even thousands of second messenger molecules e.g. α and β adrenoceptors that bind to noradrenaline G-protein-coupled receptors (GPCR) Tyrosine kinases receptors Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines (phosphorylation) A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Mediates the first steps in signaling by processes E.g. insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor β (TGF β), and many other trophic hormones 6  10/10/2023 Tyrosine kinases receptors Signal molecules bind to the extracellular domains of receptor tyrosine kinase → two receptor molecules to dimerize → brings the cytoplasmic tails of the receptors close to each other → causes the tyrosine kinase activity of these tails to be turned on → autophosphorylation Ion channel receptors Many of the most useful drugs in clinical medicine act on ion channels An ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor → voltage-gated ion channel Voltage-gated ion channels do not bind neurotransmitters directly but are controlled by membrane potential; such channels are also important drug targets Drugs that regulate voltage- gated channels typically bind to a site of the receptor different from the charged amino acids that constitute the “voltage sensor” domain of the protein used for channel opening by membrane potential 7  10/10/2023 Voltage-Gated Ion Channels Ion channel receptors For ligand- gated ion channels, drugs often mimic or block the actions of natural agonists → ligand-gated ion channel Natural ligands of such receptors include acetylcholine, serotonin, GABA, and glutamate; all are synaptic transmitters Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane E.g. acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor (nAChR), which allows Na+ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential → depolarization 8  10/10/2023 Ligand-Gated Ion Channels Transduction Cascades of molecular interactions relay signals from receptors to target molecules in the cell Transduction usually involves multiple steps Multistep pathways can amplify a signal (a few molecules can produce a large cellular response) Multistep pathways provide more opportunities for coordination and regulation 9  10/10/2023 Transduction The molecules that relay a signal from receptor to response are mostly proteins Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a conformational change Phosphorylation & dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylation Dephosphorylation - phosphatase enzymes remove the phosphates This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off 10  10/10/2023 Transduction – Small molecules and ions as second messengers The extracellular signal molecule that binds to the membrane is a pathway’s “first messenger” Second messengers are small, non-protein, water- soluble molecules or ions can readily spread throughout cells by diffusion participate in pathways initiated by G-protein-linked receptors & tyrosine kinase receptor cAMP Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal Many signal molecules trigger formation of cAMP Other components of cAMP pathways are G proteins, G-protein-linked receptors, and protein kinases cAMP usually activates protein kinase A, which phosphorylates various other proteins Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase 11  10/10/2023 Calcium ions and inositol triphosphate (IP3) Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as second messengers A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol 12  10/10/2023 Response Cell signaling leads to regulation of cytoplasmic activities or transcription The cell’s response to an extracellular signal is sometimes called the “output response” Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or may involve action in the nucleus Many pathways regulate the activity of enzymes Response Many other signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus The final activated molecule may function as a transcription factor Multistep pathways have two important benefits: Amplifying the signal (and thus the response) Contributing to the specificity of the response 13  10/10/2023 The specificity of cell signaling Different kinds of cells have different collections of proteins These differences in proteins give each kind of cell specificity in detecting and responding to signals The response of a cell to a signal depends on the cell’s particular collection of proteins Pathway branching and “cross-talk” further help the cell coordinate incoming signals Scaffolding proteins are large relay proteins to which other relay proteins are attached Scaffolding proteins can increase the signal transduction efficiency Termination of signal Inactivation mechanisms are an essential aspect of cell signaling When signal molecules leave the receptor, the receptor reverts to its inactive state 14 10/10/2023 15