Cell Signaling by Chemical Messengers PDF

Learning Objectives: Describe the general features of chemical messenger systems. Differentiate between endocrine, paracrine, and autocrine signaling. Understand the different types of messengers. Discuss how intracellular signaling modulates TFs. Describe signal transduction pathways from cell...

Learning Objectives: Describe the general features of chemical messenger systems. Differentiate between endocrine, paracrine, and autocrine signaling. Understand the different types of messengers. Discuss how intracellular signaling modulates TFs. Describe signal transduction pathways from cell surface receptors to the nucleus. Discuss the classes of membrane receptors and how they initiate signals. Explain a single receptor’s ability to signal in multiple pathways. Illustrate GPCR signal transduction. Identify second messengers and their roles in signal transduction. Explain signal termination and its importance to regulation. Features of a Chemical Messenger Pathway: Secreting cell releases a chemical messenger, transported to target cell, binds to receptor, elicits a response, signal is terminated. E.g. Nervous system- cells receive signal via an action potential, transmitter vesicles released w/ Ca influx, vesicles fuse w/ membrane & release content, diffuse to next cell & bind receptors. Receptor Action- ligand binding causes conformational change, alters protein function, pore is open. (requires binding to both subunits in order to function.) Clinical Correlation: generalized muscle fatigue, muscles of speech, eyelids droop, ↑ severity. Findings- diagnosis of myasthenia gravis, pt is producing antibodies against acetylcholine receptors, reducing signaling at neuromuscular junction. ↓ degradation of neurotransmitters→ an increase in local conc. & % of activated receptors. (so there will be less receptors than can still be activated) Differentiate Signaling Types: Endocrine- hormones secreted into blood, via pores in endothelium. Paracrine- secrete into extracellular space, to nearby cells. Autocrine- secretion chemical messenger acts on the same cell type or the cell itself. Different Types of Messengers: Neurotransmitters- small nitrogen-containing molecules, secreted into synaptic clefts or blood. Cytokines- small proteins, kill invading organisms, activate transcrip. of genes used in immune response. Ex. interferons, TNF, interleukins. Eicosanoids- derivative of arachidonic acid/similar FAs, involved in injury response, made by most cell types. (paracrine/autocrine sig.) Ex. endothelial cells secrete prostacyclin, → smooth muscle relaxation leads to vasodilation. Hormones- secreted by endocrine cells, polypeptide hormones(insulin) catecholamines(epi.) steroid(from cholesterol) Thyroid(from tyrosine). Steroid-thyroid family- lipophilic, travel in blood bound to carrier proteins(albumin mainly, corticosteroid binding globulin, thyroid binding globulin etc..), Cross plasma mem. to reach intracellular receptors. How Intracellular signaling modulates TFs: Receptor types- cell surface, intracellular(cytoplasmic/nuclear), all change cell function, many change gene expression. Signal Transduction from Cell Surface Receptors to Nucleus: Cell surface receptors interact w/ extracel. environment, bind signaling molecule, conformational change, initiates signaling pathway. Signaling is unidirectional (up or downstream). Membrane Receptor Classes: Ion-channel receptors/transporters. Receptors w/ 2nd messengers. Receptor Protein kinases- all use signal transduction to alter gene expression or other functions. 1. JAK/STAT(receptors bind JAK, signal w/ STAT)- binds cytokine, dimerize, bind JAKs which phosphorylate each other & receptor, STAT bind receptor, phosphorylated by JAK, STATs dimerize & go to nucleus to affect transcription. Ex. Interferons/Interleukins(immune), Erythropoietin(RBC prod.), Leptin(body fat mass), Growth H(stimulate IGF-1 & growth). 2. Serine-threonine kinases(use smad proteins)- ligand binds type 2 receptor, which binds & phosphorylates type 1, activated type 1 phosphorylates R-Smad, R-Smad + Co-Smad complex goes to nucleus to affect gene expression. 3. Tyrosine kinase(use Src Homology 2 domain proteins)- GF binds, receptor dimerizes, auto-phosphorylated. Adaptor proteins bind using SH2 domain, other proteins bind the adapter protein. GEF cause Ras to bind GTP instead of GDP, conformational change, Raf binds(to ras), starts MAP-K cascade(into the Nucleus). Insulin Receptor- bound receptor auto-phosphorylates, Insulin receptor substrate(IRS) binds & is phosphorylated. Various other proteins bind & are activated. Ex. of activated protein, PI-3 K, converts PIP2 to PIP3 in membrane. Protein Kinase B(activated by PDK1) acts on enzymes, alters metabolism. *Note, Some targets produce 2nd messengers, some start signaling to nucleus. A Single Receptor can Signal in Multiple Pathways: Insulin Receptor: insulin binds, PI-3 K increases PIP3 in membrane, which activates PKB, alters glucose metabolism. Vesicles w/ GLUT4 in membrane, fuse to muscle/adipose cell membrane, ↑ glucose uptake. Gene expression patterns can be altered. (e.g p70 downstream effector activated by PDK) Note* Insulin receptor already dimerized, doesNOT do that after substrate binding. GPCR Signaling: G-protein coupled receptor- binds small molecules & peptides. Changes conc. of 2nd messengers, normally in very low conc.(easy to sense changes), Greatly amplify signal. Ligand binds, GTP replaces GDP on 𝝰 subunit, GTP-𝝰 moves in the membrane to bind adenylyl cyclase, produces cAMP, GTP hydrolyzed to GDP, enzyme release, receptor complex reforms. cAMP life cycle- it’s made from ATP(so energy is lost), cAMP levels don’t remain high, cleaved to AMP by cAMP phosphodiesterase(PDE, activated by some 𝜷-𝜸 complexes) 2nd Messengers: cAMP- used in many signaling pathways. Proteins are NEVER classified as 2nd messengers. DAG-IP3: some GPCRs signaling by activating PLC. IP3 binds sarcoplasm & ER, stimulate release of Ca2+ activate proteins w/ calcium-calmodulin complex(protein kinases). Signal Termination & its Importance to Regulation: Diffusion degradation(messenger diffuse away, degraded) No available receptors, either occupied, down-regulated, or phosphate removed(GTPase). 2nd messengers lost. Any step in pathway may be blocked or “maxed out” Ras Activation/termination of signal.