CELL SIGNALLING

1 EJC H2 Biology T2W4 Cell Signalling Cell Signalling 1. Introduction The study of cell communication focuses on how a cell gives and receives messages with its environment and with itself. Cells do not live in isolation. In fact, their survival hinges on receiving and processing information from the external environment. In multicellular organisms, cell communication takes the form of cell signalling. Cell signalling is the fundamental process by which specific information is transferred from the cell surface to the cytosol and ultimately to the nucleus, leading to changes in gene expression. As such, cell signalling allows for specialisation of groups of cells. Multiple cell types can then join together to form tissues such as muscle, blood, and brain tissue. Disruption of cell signalling processes can have significant i mpacts on cell physiology. Alteration of cell signalling by neurotoxicants may be linked to transient functional impairment or to long -term changes, resulting in permanent behavioural impairments. 2. Learning Outcomes 3 (m) Outline the main stages of cell signaling: i. Ligand-receptor interaction ii. Signal transduction (phosphorylation cascade and signal amplification) iii. Cellular response (change in gene expression) (Knowledge of intracellular receptors is not required) 3 (n) Explain the roles and nature of second messengers (including cyclic AMP) 3 (o) Explain the role of kinases and phosphatases in signal amplification. 3 (p) Outline how insulin and glucagon regulate the concentration of blood glucose through the respective tyrosine kinase receptor and G-protein linked receptor. (The outline should be limited to describing how the ligand induces a conformational change in a membrane-bound receptor to trigger downstream signalling pathways that elicit physiological changes in blood glucose concentration. Details of different second messengers and specific kinases activated in the pathway are not required.) Students should be able to use the knowledge gained in this section in new situations or to solve related problems.

2 EJC H2 Biology T2W4 Cell Signalling 3. References  Campbell, N.A. and Reece, J.B. (2008). Biology, 8th edition. Pearson.  Sherwood, Fundamental of Human Physiology, 4th edition  Brooker et al., Biology, McGraw-Hill  Ho YK (2003) A-level course in Biology – Core syllabus, Longman 4. Organisation of Lecture Content Introduction 1 2. Learning Outcomes 1 3. References 2 4. Organisation of Lecture Content 3 5. Overview of Cell Signalling 3 A. Types of Cell Communication 3 B. Overview of the Stages of Cell Signalling 3 6. Mechanisms of Cell Signalling 5 I. STAGE 1: Ligand- Receptor Interaction (RECEPTION) 5 II. STAGE 2: Signal Transduction (TRANSDUCTION) 7 1. Phosphorylation Cascade 7 2. Signal Amplification 9 III. STAGE 3: Cellular Response (RESPONSE) 11 7. Types of Receptors 13 1. G-protein-coupled Receptor (GPCR) 14 1.1 Secondary Messengers 15 2. Receptor Tyrosine Kinase (RTK) 16 3. Ion Channel Receptor 18 8. Specific examples of Receptors 18 1. Glucagon and G protein signalling 18 2. Insulin and Receptor Tyrosine Kinase (RTK) signalling 20 9. Link to other topics 21

3 EJC H2 Biology T2W4 Cell Signalling 5. Overview of Cell Signaling  Cells in multicellular organisms usually communicate by releasing chemical messengers targeted for cells that are not immediately adjacent.  Some messengers travel only short distances to influence the cells in their vicinity, while other messengers travel greater distances via the circulatory system. A Types of Cell Communication  There are two types of cell-to-cell communication: 1. Direct communication which involves physical contact between interacting cells. 2. Indirect communication which involves extracellular chemical messengers or signal molecules that bind to receptors.  The study of indirect communication has led to the identification of many signalling systems. B Overview of the Stages of Cell Signalling  Cell signalling systems consists of three stages as illustrated in Fig. 2: o Stage 1: Reception o Stage 2: Signal Transduction o Stage 3: Cellular Response Synaptic Signaling (unique e.g. of paracrine signalling) Direct communication Indirect communication (short distance) Indirect communication (short distance) Indirect communication (long distance) Figure 1 Types of cell communication – Direct and Indirect.

4 EJC H2 Biology T2W4 Cell Signalling  Ligand – a signal molecule that binds specifically to another molecule, usually a receptor - Known as extracellular chemicals/ first messengers  Receptor – proteins that bind and transduce the message of the signal molecule into a cellular response.  Signal transduction – a series of steps by which signals are conveyed into the target cell where they are transformed into a cellular response  Cell signalling begins with an extracellular signalling molecule (e.g. hormones, growth factors) called a ligand.  Ligand (signal molecule) binds to a specific ligand -binding site of a protein receptor to form a ligand-receptor complex.  Ligand-binding site is structurally complementary to the ligand.  Binding of ligand to protein receptor causes a conformational change in the protein receptor which initiates signal transduction.  In signal transduction, the signal is converted to a form that can bring about a specific cellular response. Transduction can occur in a single step, or in a series of multiple steps in a signal transduction pathway.  Signal transduction pathway is mediated by intracellular signalling proteins such as kinases (that carry out phosphorylation) , or small molecules and ions such as cAMP (secondary messengers).  Multiple steps in a signal transduction pathway results in an amplification of the signal with each subsequent step.  Cellular response occurs through specific changes in cellular function, metabolism, or development (e.g . gene expression) by targeting proteins such as gene regulatory proteins, ion channels, components of a metabolic pathway, parts of cytoskeleton. Signal Transduction & Signal Amplification Reception: Ligand-receptor Interaction Cellular Response Figure 2: Diagram showing the three stages involved in cell signalling: 1. Reception 2. Signal Transduction 3. Response Figure 3: Flow chart giving the summarised details for the three stages involved in cell signalling.

5 EJC H2 Biology T2W4 Cell Signalling 6. Mechanisms of Cell Signaling I. STAGE 1: Ligand- Receptor Interaction (RECEPTION)  A specific ligand binds to the extracellular ligand-binding site of the specific receptor. This is known as reception or ligand –receptor interaction.  Ligand binding generally causes a receptor protein to undergo a change in conformation. i. For many receptors (e.g. G protein coupled receptor), this conformation change directly activates the receptor so that it can interact with another cellular molecule. ii. For other kinds of receptor s (e.g. receptor tyrosine-kinase), the immediate effect of ligand binding is more limited, mainly causing the dimerisation of two or more receptor subunits. Question Why is ligand-receptor interaction specific? Ligand is complementary in shape to the extracellular ligand binding site of the receptor. Upon binding to receptor, a specific cellular response in that specific target cell will be initiated.  There are two types of receptors that are classified based on their location in a cell: i. Cell surface receptors (focus of the syllabus)  Located on the plasma membrane.  Bind to large, polar or hydrophilic signal molecules that cannot diffuse readily ac