Cell Signaling 2024 Medical Biochemistry PDF

Medical Biochemistry THEME7 : CELL SIGNALING PATHWAYS Membrane receptors, Describe the G-protein coupled receptors, and General mechanism of signal transduction. Dr. Sheehama J.A., PhD Windhoek - 2024  Learning Ob...

Medical Biochemistry THEME7 : CELL SIGNALING PATHWAYS Membrane receptors, Describe the G-protein coupled receptors, and General mechanism of signal transduction. Dr. Sheehama J.A., PhD Windhoek - 2024  Learning Objectives: After this theme students should be able to: 1. Know the structure of membranes and the fluid mosaic model. 2. Describe the common plasma membrane receptors. 3. Describe G-protein coupled receptors. 4. Understand the functions of the main components of signal transduction pathways. 5. Outline the activation of downstream intracellular signalling cascades by heterotrimeric G-proteins. 6. Discuss the generation of second messengers and explain how they activate key protein kinases. 7. Explain how phospholipases generate a diverse array of lipid second messengers. 8. Discuss how the generation of a variety of second messengers can amplify hormone signals and leads to the generation of specific biologic responses. 9. Explain how defects in signal transduction pathways can lead to diseases.  Cell Signalling molecules and modes of cell signaling Human beings have different organs, tissues and cell types that contribute in an integrated way as the body condition changes (growth, differentiation and adapts to changing conditions). This requires communication that is carried out by chemical messengers from one cell to another in a different location interactions of cells with the ECM direct contact of one cell with another The goal of such signals is to change actions carried out in target cells (metabolic enzymes, gene regulatory proteins, ion channels, or cytoskeletal proteins) Cell Communication - No cell lives in isolation Cells communicate with each other Cells send and receive information (signals) Information is relayed within cell to produce a response There are four main classes of receptors: G-protein-coupled receptors; ligand-gated ion channels; intracellular receptors; and tyrosine kinase-coupled receptors.  Cell structure and function in transduction Plays an important role in cell signalling and communication Contains channels, carriers, pumps, receptors Cell-surface receptors come in 3 main types: ion channel receptors, GPCRs, and enzyme-linked receptors. Membrane receptors can be divided into several major groups: 1. Seven transmembrane domain G protein– coupled receptors (GPCRs), 2. Tyrosine kinase receptors, 3. Cytokine receptors, and 4. Transforming growth factor-beta (TGF-β) family serine kinase receptors. Cell G-protein-coupled receptors (GPCRs) These are integral membrane proteins containing an extracellular amino terminus, seven transmembrane α-helical domains, and an intracellular carboxy terminus. GPCRs recognize a wide variety of signals ranging from photons to ions, proteins, neurotransmitters, and hormones. Cell Signaling Process Recognition of signal Receptors Transduction Change of external signal into intracellular message with amplification and formation of second messenger Effect Modification of cell metabolism and function Cell Signalling molecules and modes of cell signaling Generally, the receptor binds only one specific chemical messenger. Each receptor initiates a signal transduction pathway that will activate or inhibit certain processes. Only target cells carry receptors for that messenger. General Cell Signaling Pathway Cell Signaling Cascades Cell Signal Recognition Performed by receptors Ligand will produce response only in cells that have receptors for this particular ligand Each cell has a specific set of receptors  Different Responses to the Same Signaling Molecule (A) Different Cells Acetylcholine (ACh) regulates the minute-to-minute changes in heart rate and contractility required for proper cardiovascular function via muscarinic receptors, opposing the activity of the sympathetic nervous system  Signalling molecules and modes of cell signaling Cells can respond to a signal if they have a specific receptor for that signal. Signal transduction: process by which a biological cell converts one kind of signal or stimulus from one form into another. Signal transduction pathway : a biochemical sequence of events and chemical reactions that lead to a cellular response, following the cell receptor’s activation by a signal. Amplification - Signalling molecules and modes of cell signaling Amplification  Signalling molecules and modes of cell signaling Chemical Messenger System A chemical message is any compound that serves to transmit a message, and may refer to: Hormone, long range chemical messenger. Neurotransmitter, communicates to adjacent cells. Neuropeptide, a protein sequence which acts as a hormone or neurotransmitter. Neurotransmitters are your body’s chemical messengers and carry messages from one nerve cell across a space to the next nerve, muscle or gland cell. These messages help you move your limbs, feel sensations, keep your heart beating, and take in and respond to all information your body receives from other internal parts of your body and your environment.  Home work 3 Due: 26/09/2024, @ 07:30 1. Describe in details functions of the main components of signal transduction pathways. 20 2. List and explain signal transduction related diseases. 10  Signalling molecules and modes of cell signaling Acetylcholine (ACh) receptors Voltage-gated and ligand-gated ion (nicotinic acetylcholine receptor) at channels in neural transmission the neuromuscular junction Signalling molecules and modes of cell signalling Results of response to signalling  Signalling molecules and modes of cell signaling Main signaling components Ligands (Primary/First messengers) Receptors Second Messengers Key steps in signal transduction Release of the primary/first messenger Reception of the primary messenger Delivery of the message inside the cell by the second messenger  Signalling molecules and modes of cell signaling Mechanisms of intercellular communication Direct through gap junctions Indirect-messengers/ligands Signalling molecules and modes of cell signaling Types of Messengers/ligands (First messengers)  Signalling molecules and modes of cell signaling Hydrophilic and hydrophobic first messengers Hydrophobic ligands Hydrophilic ligands Steroid hormones (progesterone, testosterone, neurotransmitters (acetylcholine, estrogen), thyroid hormone, retinoic acid, and epinephrine, Histamine ) and peptide hormones vitamin D (insulin, glucagon) Transported in the blood bound to serum Transported in blood stream and present in tissue albumin. fluid Diffuse across the plasma membrane and bind to binding to cell surface receptors, many of which receptors in the ligand sensitive target cell are ligand gated ion channels  Signalling molecules and modes of cell signaling Receptors May be classified according to location and activity Cytoplasmic and nuclear receptors found in the cytosol and nucleus (e.g steroid hormone receptors) Membrane receptors span membrane and bind ligand outside the cell (e.g. peptide hormone receptors) Ion channel receptors membrane proteins which change shape when ligand binds (e.g. acetylcholine receptor) G-protein coupled receptors Different Responses to the Same Signaling Molecule (B) One Cell but, Different Pathways Hypoglycemia Glucagon secretion Hepatocyte: Glucagon/receptor binding Second messenger: cAMP Response: Enzyme phosphorylation P P Glycogen synthase Glycogen phosphorylase (Inactive form) (Active form) Inhibition of glycogenesis Stimulation of glycogenolysis  GTP-Dependant Regulatory Proteins (G-Proteins) G-Proteins: Trimeric membrane proteins (αβγ) G-stimulatory (Gs) and G-inhibitory (Gi) Binds to GTP/GDP Forms of G-Proteins Inactive form Active form Trimeric –bound GDP α-bound GTP (αβγ/GDP) (α/GTP) The α-subunit has intrinsic GTPase activity, resulting in hydrolysis of GTP into GDP and inactivation of G-proteins  Signalling molecules and modes of cell signaling Modes of signaling Endocrine - the cell secretes a signal which travels to and stimulates a response in distant cells Example: hormones  Signalling molecules and modes of cell signaling Modes of signaling Paracrine - the cell secretes a signal which diffuses to and stimulates a response in nearby cells Signals are usually neurotransmitters (Acetylcholine)  Signalling molecules and modes of cell signaling Modes of signaling Autocrine - the cell secretes a signal which can bind on its own membrane and stimulate a response example: immune mediated responses  Signalling molecules and modes of cell signaling Major signaling systems in the body.  Signalling molecules and modes of cell signaling G-protein coupled receptors (GPCR) Seven-transmembrane domain receptors, 7TM receptors, Heptahelical receptors, serpentine receptors. Largest family of cell surface receptors (Gs, Gi/Go, Gq and G12) Transmembrane receptors with 7 alpha helices that span the membrane Intracellularly bound to G-protein (Guanine nucleotide binding protein) - link membrane receptors to their intracellular molecular effectors. G-protein coupled receptors and G-protein signalling G-protein coupled receptors Signal termination step Hydrolysis of GTP to GDP inactivates the α-subunit which re-associates with the β,γ complex Regulated by GTPase activating proteins (GAP proteins) G-protein coupled receptors and G-protein signalling Signaling Pathways for Regulation of Metabolism Two important second messenger systems: Adenylyl cyclase system - a key second messenger that regulates diverse physiological responses including sugar and lipid metabolism, olfaction, and cell growth and differentiation. Calcium/phosphatidylinositol system - One of the most ubiquitous signal transduction mechanisms is the phosphoinositide-calcium messenger system, which is activated by hormones.  Adenylyl cyclase Adenylyl cyclase: Membrane-bound enzyme and Converts ATP to cAMP Activation/Inhibition: Signal: Hormones or neurotransmitters (e.g., Glucagon and epinephrine) or toxins (e.g., Cholera and pertussis toxins) Receptor: G-protein coupled receptor Response: Activation/inhibition of protein kinase A (cAMP-dependent protein kinase) cAMP is able to regulate gene expression, aggregation, cellular differentiation, and cell growth. The adenylyl cyclase pathway is known as the cAMP- dependent pathway because it relies on cAMP to employ its effects. The adenylate cyclase function and cAMP pathway are important because they mediate many processes crucial for maintaining life in living things. Many responses in the human body, such as heart rate regulation and memory retention in the brain, are cAMP-AC dependent. Signal Transduction: Adenylyl Cyclase System Resting state: No Signal Ligand/Receptor Binding Activation of Gs-protein Activation of adenylyl cyclase Adenylyl Cyclase System: cAMP-Dependent Protein Kinase (Protein Kinase A) 1 AMP 1Phosphodiesterase Termination of Signal (A) 1 AMP Protein phosphatase Phosphodiesterase cAMP Inactive protein kinase 1Phosphodiesterase Termination of Signal (B) Termination of Signal (C) Х G-Protein Coupled Membrane Receptor  Regulation of Glycogen Metabolism by Glucagon: Effects on Glycogen Synthase and Phosphorylase Hypoglycemia Glucagon secretion Hepatocyte: Glucagon/receptor binding Second messenger: cAMP Response: Enzyme phosphorylation P P Glycogen synthase Glycogen phosphorylase (Inactive form) (Active form) Inhibition of glycogenesis Stimulation of glycogenolysis Pyruvate Kinase Regulation: Covalent Modification Calcium/Phosphatidylinositol System Calcium/Phosphatidylinositol System Diacylglycerol (DAG) Phospholipase C Inositol Trisphosphate (IP3) e.g., Antidiuretic hormone (ADH) Acetylcholine Intracellular Signaling by Inositol trisphosphate Signal Amplification Take away notes or message on cell signaling Cell signaling allows Signal transmission and amplification Regulation of metabolism Intercellular communications & coordination of complex biologic functions  Second messengers, signal transduction and disease Intracellular messengers generated through the binding of first messengers to receptors extracellularly Carry out intracellular signal transduction Examples: Cyclic nucleotides (cAMP, cGMP) Calcium, DAG, and IP3 Nitric Oxide Second messengers, signal transduction and disease General characteristics of secondary messengers: short lived the message carried depends on messenger concentration. affect downstream targets which are usually enzymes. (change the concentration of the enzymes or their activity) when the messengers are degraded the message gets terminated. Second messengers, signal transduction and disease Cyclic nucleotides second messengers What body functions do nerves and neurotransmitters help control? Your nervous system controls such functions as your: Heartbeat and blood pressure. Breathing. Muscle movements. Thoughts, memory, learning and feelings. Sleep, healing and aging. Stress response. Hormone regulation. Digestion, sense of hunger and thirst. Senses (response to what you see, hear, feel, touch and taste). They include: Serotonin, Dopamine, Glutamate, and Acetylcholine. Second messengers, signal transduction and disease  Amino acids neurotransmitters These neurotransmitters are involved in most functions of your nervous system. Glutamate. This is the most common excitatory neurotransmitter of your nervous system. It’s the most abundant neurotransmitter in your brain. It plays a key role in cognitive functions like thinking, learning and memory. Imbalances in glutamate levels are associated with Alzheimer’s disease, dementia, Parkinson’s disease and seizures. Gamma-aminobutryic acid (GABA). GABA is the most common inhibitory neurotransmitter of your nervous system, particularly in your brain. It regulates brain activity to prevent problems in the areas of anxiety, irritability, concentration, sleep, seizures and depression. Glycine. Glycine is the most common inhibitory neurotransmitter in your spinal cord. Glycine is involved in controlling hearing processing, pain transmission and metabolism.  Monoamines neurotransmitters Monoamines neurotransmitters regulate consciousness, cognition, attention and emotion. Serotonin. Serotonin is an inhibitory neurotransmitter. Serotonin helps regulate mood, sleep patterns, sexuality, anxiety, appetite and pain. Diseases associated with serotonin imbalance include seasonal affective disorder, anxiety, depression, fibromyalgia and chronic pain. Histamine. Histamine regulates body functions including wakefulness, feeding behavior and motivation. Histamine plays a role in asthma, bronchospasm, mucosal edema and multiple sclerosis. Dopamine. Dopamine plays a role in your body’s reward system, which includes feeling pleasure, achieving heightened arousal and learning. Dopamine also helps with focus, concentration, memory, sleep, mood and motivation. Diseases associated with the dopamine system include Parkinson’s disease, schizophrenia, bipolar disease, restless legs syndrome and attention deficit hyperactivity disorder (ADHD). Many highly addictive drugs (cocaine, methamphetamines, amphetamines) act directly on the dopamine system. Epinephrine. Epinephrine (also called adrenaline) and norepinephrine are responsible for your body’s so-called “fight-or-flight response” to fear and stress. Too much epinephrine can lead to high blood pressure, diabetes, heart disease and other health problems. As a drug, epinephrine is used to treat anaphylaxis, asthma attacks, cardiac arrest and severe infections. Norepinephrine. Norepinephrine (also called noradrenaline) increases blood pressure and heart rate. It’s most widely known for its effects on alertness, arousal, decision-making, attention and focus.  Peptide neurotransmitters Endorphins. Endorphins are your body’s natural pain reliever. They play a role in our perception of pain. Release of endorphins reduces pain, as well as causes “feel good” feelings. Low levels of endorphins may play a role in fibromyalgia and some types of headaches. Acetylcholine This excitatory neurotransmitter does a number of functions in your central nervous system and in your peripheral nervous system. Acetylcholine is released by most neurons in your autonomic nervous system regulating heart rate, blood pressure and gut motility. Acetylcholine plays a role in muscle contractions, memory, motivation, sexual desire, sleep and learning. Imbalances in acetylcholine levels are linked with health issues, including Alzheimer’s disease, seizures and muscle spasms.  Second messengers, signal transduction and disease DISORDER/CONDI COMMENTS TION Myasthenia gravis Autoantibodies to the acetylcholine receptor, leading to neuromuscular dysfunction. Cholera Bacterial-derived toxin leads to disease, including hypovolemic shock. Treat with a glucose-electrolyte solution to increase coupled glucose-sodium uptake into the intestinal epithelial cells, reversing the loss of water from these cells. Anorexia nervosa Effects of inadequate nutrition on hormone release and response. Cortisol, glucagon, and epinephrine levels are all increased under these conditions. Heart failure and Treat with drugs that inhibit cGMP phosphodiesterase. e.g. erectile dysfunction sildenafil (viagra).  Questions?? ? Thanks……………! 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