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Lecture 9

Lecture 9 - Basic Principles of cell signaling.docx

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Biology 2382B
Cumming/ Damjanovski

Lecture 9: Basic principles of cell signaling and GPCR system Learning Objectives • Basic elements of cell signaling • Signaling through intracellular receptors • Signaling through cell-surface receptors • G protein coupled receptor system – GPCR, G proteins, types of Ga, effectors, second messengers • FRET Signal Transduction – Signal transduction: Conversion of a signal into another – What stimulates signal transduction? o Involves chemical stimuli i.e. growth factors, cytokines, hormones, ECM, neurotransmitters and physical stimuli i.e. light, sound, etc. – Very important - Incredibly “hot” area; over 300,000 papers published – All aspects of normal development & physiology – from birth to death. – Malfunction initiates diseases – “cancer, heart, diabetes” • Happens all the time in our bodies and need to happen in a controlled manner in order to keep things functioning. • Most of the drugs that people take function through signal transduction Some of the Players not an exhaustive list: • Receptor Tyrosine Kinases (RTKs) • Mitogen Activated Protein Kinases (MAPK) • G-protein coupled receptors (GPCRs) • Proto-oncogenes (Ras) Basics – A signal is a molecule either a ligand or primary messenger – i.e. small molecules, hormones, small peptide  (epinephrine, acetylcholine, steroids), peptide hormones, monoamines etc. – Large molecules  growth factors, cytokines (proteins) – Receptors: actually elicit a response – Cell-surface receptors – Intracellular receptors (found inside the cell) Page 1 of 10 – In many signal pathways, there are middlemen involved between the signal and the response besides just the receptor. In a sequential series trigger the ultimate response in the cell. – Effectors: Intracellular signaling molecules and proteins – they are the middle men. – Secondary messengers: other signaling molecules usually made within the cell following the initial stimulus (primary messenger). Primary messengers start the ball rolling in the cell. Cascade of signal is generated by the production of secondary messengers in the cell. – Small organic molecules: Ca , cAMP, cGMP, IP3, DAG, NO, etc. – Made following the initial primary stimulus, these further amplify the signal. Two types of receptors There are 2 types of receptors, cell surface receptors (some entity outside of the cell) and intracellular receptors. The primary messenger, stimulus, or ligand, will determine how it will elicit its effect on the cell. • Proteins are bulky, they do not readily transverse the PM because they are hydrophilic and require an aqueous environment. The hydrophilic signaling molecules can bind to cell surface receptors for that reason. • In order for the intracellular cell receptor to work, it needs to bind a ligand. The ligand must be lipid-soluble (hydrophobic) in order to cross the membrane. Those ligands are hydrophobic but they originate from ECM and it is an aqueous environment. – Requires a carrier protein to carry it through aqueous environment. – Once at cell surface the ligand is released at the membrane and can bind the intracellular receptor to trigger a response Nuclear-receptor superfamily Steroid hormone binding receptors: • Steroids can cross the membrane because they have complex aromatic rings and hydrocarbon chains making them hydrophobic. • These steroid ligands can cross the membrane and binds the intracellular receptors protein. • Intracellular receptor proteins must have: – A ligand binding domain (where it binds the steroid) – DNA binding domain, can bind certain sequences of DNA within the DNA. • Can be found in different parts of the cell. – Some are in the cytoplasm others in the nucleus but they can all be function in the nucleus. Page 2 of 10 Gene activation by a nuclear receptor • Glucocorticoid: is a hormone with anti-inflammatory properties. It has the ability to cross the membrane. It can then bind the glucocorticoid receptor in the cell. • Glucorticoid receptor: normally found in the cytoplasm because it has an inhibitor protein that can bind to it. (HSP90) • HSP90: glucocorticoid receptor inhibitor protein. Binds to LBD of glucocorticoid receptor. Binding keeps receptor localized to the cytosol – it can’t get into the nucleus. • Glucorticoid presence – binds LBD of glucocorticoid receptor and kicks off HSP90. – Allows translocation of glucocorticoid receptor to the nucleus. • Once in nucleus it can dimerize with another glucocorticoid receptor. – Dimeric complex allows DNA binding domains to bind to the glucocorticoid response elements • Glucorticoid response elements: sequences found within the genome that are upstream of genes (promoter or regulator region) where it affects the expression of the gene (most likely increases). How does GR dimer affect gene expression? • Binding to the glucocorticoid response elements will result in the exposure of the activation domains. • Activation domains help recruit transcription factors which leads to increased expression of that gene. This process is a somewhat quick way to activate gene expression through ligand binding to intracellular receptor and activating gene expression. Basic Concepts of Signal transduction For a cell surface receptor, a primary messenger (usually a protein but could be an organic molecule. Cell surface receptor must have: – Extracellular domain – a portion that sticks out outside the cell – Transmembrane domain – Cytosolic domain Ligand binding causes conformational change. Can cause some activity at the cytosolic domain itself or protein interactions that elicit a chain of events. i.e. proteins from the cytosol now come close to the cell surface receptor. Page 3 of10 • Ultimately results in an effect carried out by the effector protein. i.e. increase of a metabolic enzyme which leads to altered metabolism or a cytoskeleton protein that can change the cell shape. Four forms of intercellular signaling There are cells that produce ligands and other cells that respond to ligands. 1. Endocrine signaling: – There are glands that can produce a hormone that enters the bloodstream. – Through a carrier it is transported to a distant area in the body and released onto a target cell. 2. Paracrine signaling: – Short distance between the cell making the stimulus to the cell responding to the stimulus – i.e. neurons in your brain make neurotransmitter, a neuron in close proximity responds to neurotransmitter via a neurotransmitter receptor. 3. Autocrine signaling: – Self-stimulating scenario. Cell makes the ligand or stimulus and makes the receptor for that ligand. – The cell responds to its own ligand. 4. Cell-cell signal: – Cells adjacent to each other are physically linked to each other. – Linked via signaling molecules i.e. transmembrane protein that has an extracellular portion that sticks out and touches onto the adjacent cells. It touches a receptor on the adjacent cell to induce a response. • Some signaling molecules can work across different forms of intracellular signaling i.e. growth factor Signaling by cell-surface receptors Example: Signaling cell releases signaling molecule (primary messenger) onto a responding cell receptor. The ligand binding induces a conformation change in the receptor where the cytoplasmic domain is altered and triggers signaling events. The cellular response can vary: • Short-term cellular response: activating molecules that will affect pre-existing proteins hanging around waiting for instruction. This signal leads to alteration of activity of the protein. Page 4 of10 • Long-term cellular response: Relies on a lot of middlemen to trigger gene expression. Takes longer to trigger the response but generally tends to lasts longer. • Termination of cellular response: When you are turning something on it needs to be turned off eventually. Turning on something indefinitely is not a good thing. Termination relies on auto- feedback mechanism. Fast response: • Leads to direct alteration of a cytosolic protein • Happens within milliseconds to few minutes. • Types of proteins are involved in ion transport, secretion, metabolism, cell movement, i.e. neurotransmitters are very quick • Quick to turn on, quick to turn off Slow response: • Usually relies on a transcription factor to increase the expression of a gene. Long process. – mRNA transcript  transcriptional apparatus  make proteins fold protein • Can take minutes to hours to turn on. • Proteins are usually involved in cell growth and division. • Slow to turn on and slow to be turned off. Multiple types of cell signals in Animals • Trophic signals or Trophic factor support: Signals that tell the cell everything is fine, keep g
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