Week 5 - Signalling PDF

Dr Katja Vogt Cell signalling Cell signalling Learning objectives  Dr Katja Vogt Cell signalling Cell signalling General principles Receptors Intracellular...

Dr Katja Vogt Cell signalling Cell signalling Learning objectives  Dr Katja Vogt Cell signalling Cell signalling General principles Receptors Intracellular signalling molecules Feedback and complex signalling Dr Katja Vogt  Dr Katja Vogt Principals of cell signalling Extra-cellular Reception Transductio Response n Intra-cellular Twitter: @katjetz E-mail: [email protected] Intra-cellular BSc Medical Sciences  Dr Katja Vogt Principles ofReception Cell signalling Transductio n Response Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Characteristics of signalling 1. Specificity 2. Amplification 3. Network 4. Feedback Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences signalling Dr Katja Vogt Juxtacrine (contact dependent) Paracrine (can be autocrine) Synaptic Endocrine Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Hormones proteins (eg, adrenocorticotrophin) Glycosylated (eg, thyroid-stimulating hormone) and/or dimerized (eg, follicle-stimulating hormone) Receptors on the peptides (eg, vasopressin) membrane monoamines (eg, norepinephrine) amino acid derivatives (eg, melatonin) steroids (eg, cortisol) In the lipids (eg, prostaglandins) nucleus Exceptions: triiodothyronine activates classic thyroid hormone receptors in the nuclear compartment and the trace amine receptor (TAR1) on the cell surface and oestrogen to activates both types of receptor Twitter: @katjetz 9 E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Hormone synthesis Proteins and peptides - Lipid based Hormones - classical DNA-mRNA- synthesis through precursors (cholesterol) protein route Twitter: @katjetz 10 E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Mineralcorticoids Progestogens (C21) (C21) Glucocorticoids (C19) Androgens (C21) 18) (C gens ro Est  Dr Katja Vogt Role of cell organelles in hormone synthesis Cells that secrete steroid Peptide hormones secreting hormones contain abundant cells contain abundant rough smooth endoplasmic endoplasmic reticulum (RER) reticulum (SER) Twitter: @katjetz 12 E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Cells secreting peptide hormones Example: α cells and β cells in the islet of Langerhans @katjetz 13 [email protected]  Dr Katja Vogt Reception Examples Most ligands Steroid hormones, Thyroid hormones,  Dr Katja Vogt Slow and fast responses  Dr Katja Vogt Nuclear Receptors In the nucleus or cytoplasm Regulate gene transcription Usually have three distinct domains: Ligand-Binding Domain DNA – Binding Domain Activation Function Domain(s) Steroids and lipid based ligands Exceptions: Triiodothyronine (T3) Oestrogen Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Steroid receptors prototypical cortisol receptor under basal conditions, exist as cytoplasmic, multimeric complexes with Heat Shock Noeth 2012 Proteins of Association (HSP) the steroid ligand with the receptor results in dissociation of the HSP —> nuclear translocation signal of receptor Binds to the specific DNA elements (HRE), which is also supported/ determined by enhancer elements away from the binding site Twitter: Or: E-mail: @katjetz binds to other transcription factors to repress [email protected] 1 BSc Medical Sciences 7  Dr Katja Vogt Triiodothyronine - signalling Acts on gene regulation On nuclear and mitochondrial genes By binding to thyroid receptor (TR) and recruiting coactivators Brent 2012 Twitter: @katjetz 18 E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Triiodothryronine signalling T3 signals through “traditional” pathways and directly on gene regulation On nuclear and mitochondrial genes By binding to thyroid receptor (TR) and recruiting coactivators Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Major classes of cell surface receptors  Dr Katja Vogt 1. Ion-channel coupled receptors Examples Acetylcholine receptor (AChR) GABA receptors Glutamate receptors Serotonin receptors Ligand-gated channels Voltage-gated channels Mechanically-gated channels Also known as transmitter-gated ion channels, ligand-gated ion channels or inotropic receptors Rapid synaptic signalling Mediate most forms of electrical signalling in the nervous system  Dr Katja Vogt 2. G-protein coupled receptors Seven-transmembrane domain receptor & Trimeric GTP-binding protein (G-protein) Target protein can be enzyme or also ion channel Largest family of cell-surface receptors Linked to either cAMP or phosphoinositol signalling pathway Examples Rhodopsin Olfactory receptors Serotonin  Dr Katja Vogt Some trip wires… Two classes of GABA receptors: GABAA and GABAB. – GABAA receptors  ligand-gated ion channels – GABAB receptors  G protein-coupled receptors Serotonin and Acetylcholine receptors have both ligand gated ion channel and G-coupled receptors within their family  Dr Katja Vogt Three different G proteins Gs proteins Gi proteins Gq proteins Adenyla Adenyla te te PLC cyclase cyclase cAMP DA IP3 G Stimulate adenylate Inhibit adenylate Activate phospholipase C cyclase (↑ cAMP) cyclase (↓ cAMP) (↑PKC, ↑[Ca2+]i) Examples Examples Examples β-adrenergic receptors α2-adrenergic α1-adrenergic receptor for receptors M2 receptors M1 adrenocorticotropic muscarinic receptors muscarinic receptors hormone (ACTH) opioid receptors vasopressin receptor  Dr Katja Vogt Adrenergic Receptors Group of G coupled receptors Subgroups: – Alpha receptors: a1  Gq protein coupled a2  Gi protein coupled – Beta receptors: b1, b2, b3 all Gs coupled Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  TSH Dr Katja Vogt TSH signalling Causes increased synthesis and secretion of thyroxine Transient effect via diacyl glycerol (DAG) Persistent effect via cAMP Calebrio 2010 Twitter: @katjetz E-mail: [email protected] 2 BSc Medical Sciences 6  Dr Katja Vogt 3. Enzyme coupled receptors Function as or associate with Examples enzymes (often kinases) Growth Factor Receptor Insulin receptor Heterogeneous, mostly single Ephrin transmembrane protein Cytokine receptors Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Major classes of cell receptors Or Hyperpolarisation or Ca2+ release Protein phosphorylation depolysarisation Protein phosphorylation Gene transcription Other Protein synthesis Timescale Timescale Timescale Milliseconds Seconds Hours Examples Examples Examples Nicotinic Muscarinic Growth factor receptors ACh receptor ACh receptor Cytokine receptors  Dr Katja Vogt Intra-cellular signalling molecules Relay signals received at receptors, ultimately resulting in signalling cascade Transduce and integrate signals before relaying a signal forward Intra-cellular signalling complexes enhance the speed, efficiency and specificity of the response  Dr Katja Vogt Phosphorylation  Dr Katja Vogt Phosphorylation ⭐ The covalent addition of a phosphate (phosphoryl)group to a molecule. Activation Deactivation Passing on the signal (molecular switches)  Dr Katja Vogt Molecular switches Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Complexity of the system Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Three types of intracellular signalling complexes On a scaffold proteins  Dr Katja Vogt Complex signalling Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Feedbac k Positive feedback Can generate an All-or-None response Output stimulate its own production Negative feedback Output inhibits its own production and limits the level of response If its long enough delays it can produce oscillated responses Adjustment to sensitivity to a signal Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences  Dr Katja Vogt Desensitisation Desensitisation in Pharmacology is the reduction of activity of a drug target in response to a drug 3 7  Dr Katja Vogt Complex signalling On a scaffold proteins  Dr Katja Vogt Insulin signalling @katjetz 41 [email protected]  Dr Katja Vogt Insulin signalling Heterotetrameri c insulin receptor Ligand binding leads to activation of intrinsic tyrosine kinase and thus tyrosine phosphorylation Associated proteins insulin receptor substrate (IRS 1-4) bind and get phosphorylated Form platforms for additional signalling molecules, including PI-3 kinase, GRB2, and mTOR Each of these cascades may influence different biologic processes All phosphorylation events are reversible through the action of specific phosphates @katjetz 42 [email protected]  Dr Katja Vogt Cell signalling MBBS Learning Describe the principles of cell signalling outcomes: @katjetz [email protected] BSc Medical Sciences  Dr Katja Vogt Reading list “Essential Cell Biology”- Alberts, B. et al. 2014 Chapter 16 (signalling) 17 (cell cycle) 18 (apoptosis) Apoptosis: A Review of Programmed Cell Death Susan Elmore, Toxicol Pathol. PMC 2007 Dec 6. doi: 10.1080/01926230701320337 Reisner HM. Cell Injury, Cell Death, and Aging. In: Reisner HM. eds. Pathology: A Modern Case Study New York, NY: McGraw-Hill;. http://accessmedicine.mhmedical.com/content.aspx? bookid=1569&sectionid=95968199. Accessed October 09, 2018. Chapter 2 Chapter 3. The Nucleus & Cell Cycle. In: Paulsen DF. eds. Histology & Cell Biology: Examination & Board Review, 5e New York, NY: McGraw-Hill; 2010. http://accessmedicine.mhmedical.com/content.aspx?bookid=563&sectionid=42045296. Accessed October 09, 2018. Clinical Cytogenetics. In: Schaefer G, Thompson, Jr. JN. eds. Medical Genetics: An Integrated Approach New York, NY: McGraw-Hill;. http://accessmedicine.mhmedical.com/content.aspx? bookid=2247&sectionid=173744189. Accessed October 12, 2018. Meisenberg, Gerhard, PhD; Simmons, William H., PhD; Principles of Medical Biochemistry , Chapter 19, 316-340 Twitter: @katjetz E-mail: [email protected] BSc Medical Sciences