YIJC [H2] CI3.3 Cell Signalling (N)(S)(vetted)

2025 JC2 BIOLOGY LECTURE NOTES CORE IDEA 3: ENERGY AND EQUILIBRIUM TOPIC 3.3: COMMUNICATION AND EQUILIBRIUM IN ORGANISMS (CELL SIGNALLING) Learning Outcomes: Candidates should be able to: Core Idea 3B: Communication and Equilibrium in Organisms (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) (n) explain the roles and nature of second messengers (including cyclic AMP) (o) explain the role of kinases and phosphatases in signal amplification (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 signaling pathways that elicit physiological changes in blood glucose concentration. Details of different second messengers and specific kinases activated in the pathway are not required.) Use the knowledge gained in this section in new situations or to solve related problems. References: Reece, J. B. et al. (2018). Campbell Biology (11th Ed). Chapter 9: Cellular Signalling, pp. 214 – 231. H2

2 LECTURE OUTLINE: 1. Introduction 2. Types of Extracellular Signals 3. Stages of Cell Signalling 3.1. Stage 1: Ligand-Receptor Interaction (Reception of signal) 3.2. Stage 2: Signal Transduction 3.2.1 Second Messengers 3.2.2 Phosphorylation Cascade 3.2.3 Signal Amplification 3.3. Stage 3: Cellular Response 4. G-protein Linked Receptors (GPLRs) 4.1. Structure of GPLR 4.2. Regulation of Blood Glucose Concentration by Glucagon via GPLR 5. Receptor Tyrosine Kinase (RTK) 5.1. Structure of RTK 5.2. Regulation of Blood Glucose Concentration by Insulin via RTK 6. Advantages of Cell Signalling Pathways in Multicellular Organisms

3 1. Introduction ▪ Large multicellular organisms contain many different organs and tissue types. For all of these organs and tissues to work together as a unified whole, cell-to-cell communication is essential. ▪ Cells need to be able to receive and respond to extracellular signals. For e.g., communication between neurone and muscle cell for musc ular contraction, communication between cells of the endocrine gland and target cell for homeostatic control etc. 2. Types of Extracellular Signals ▪ Extracellular signals molecules fall into two classes. 1. The larger class of signals consists of molecules that are too large or too hydrophilic (i.e. polar OR charged) to pass through the cell surface membrane of the target cell (Relate this to the property of the phospholipid bilayer). This class of molecules relay their signals through the receptors embedded in the cell surface membrane of the target cells. For example, peptide hormones (e.g. glucagon, insulin) bind to receptors on the surface of their target cells to relay their signals. 2. The smaller class of signals consists of molecules that are small or hydrophobic (i.e. non- polar) to diffuse across the cell surface membrane into the target cells. These signal molecules either activate intracellular enzymes or bind to intracellular receptors proteins that regulate gene expression. For example, steroid hormones (e.g., cortisol, testosterone, and oestrogen) diffuse directly across the cell surface membrane of target cells, bind to an intracellular receptor before exerting its effect on gene expression. Fig. 2.1: (a) Hydrophilic signal molecule binds to membrane receptor to relay signal; (b) Hydrophobic signal molecule enters cell directly to bind to intracellular receptor. ▪ In this topic, we will focus on the larger class of signalling molecules , namely the peptide hormones glucagon and insulin.

4 3. Stages of Cell Signalling ▪ Cell signalling refers to the processes in which cells are stimulated or inhibited by extracellular signals. ▪ These extracellular signals are c alled ligands (first messengers ), since the initiate the cell signalling pathway. ▪ Cell signalling comprises of 3 stages shown in Fig. 3: 1. Stage 1: Ligand-receptor Interaction (Reception of signal) 2. Stage 2: Signal Transduction 3. Stage 3: Cellular Response Fig. 3. The three main stages of cell signalling Learning Outcomes: (m) Outline the main stages of cell signalling: i. ligand-receptor interaction ii. signal transduction (phosphorylation cascade and signal amplification) iii. cellular response (change in gene expression) (n) Explain the roles and nature of second messengers (including cyclic AMP) (o) Explain the role of kinases and phosphatases in signal amplification

5 3.1 Stage 1: Ligand-Receptor Interaction ▪ Cell surface receptors generally consist of three discrete domains: 1. an extracellular domain facing the extracellular fluid, which contains the ligand-binding site, 2. a transmembrane (membrane-spanning) domain that spans the cell surface membrane, and 3. the intracellular / c ytoplasmic domain segment facing the cytosol , which interacts with molecules within the cell. Fig. 3.1. Three domains of a cell surface receptor ▪ When a ligand arrives at the cell surface, it binds to the ligand-binding site of the receptor’s extracellular domain because the ligand has a 3D configuration that is complementary to the ligand-binding site. ▪ This explains why ligand -receptor interactions are specific. For example, the growth hormone receptor binds to growth hormone but not to other hormones. ▪ Ligand binding induces a conformational change in the receptor. This conformational change is transmitted through the transmembrane domain to the cytoplasmic domain. This results in activation of the receptor. ▪ Most cell surface receptors proteins belong to one of the three large families: 1. G-protein linked receptors (GPLR); 2. Enzyme-linked receptors (e.g., Receptor Tyrosine Kinase (RTK)); and 3. Ion channel-linked receptors (ICLR). The difference among these three classes is the type of ligands they bind to, as well as the intracellular signals generated upon receptor activation. ▪ In this topic, we will focus on G-protein l inked receptors and enzyme-linked receptor (Receptor Tyrosine Kinase).

6 3.2 Stage 2: Signal Transduction ▪ Signal transduction refers to the conversion of an extracellular signal from one physical or chemical form to another (e.g., conversion of light to a chemical signal, or of an extracellular signal to an intracellular signal), that can bring about a specific cellular response. ▪ Signal transduction occurs after activation of receptor. It requires a sequence of changes in a series of different molecules in a multi-step pathway. These molecules are called relay molecules, which are usually proteins. ▪ In a signal transduction pathway, the ligand is not passed along the pathway. ▪ The information (triggered by the conformational change in the receptor protein) is passed on via two mechanisms: 1. Production of second messengers; and 2. Phosphorylation cascades involving kinases and phosphotases. 3.2.1 Second Messengers ▪ Second messengers are substances released into the cytoplasm after the first messenger (ligand) binds to its receptor, hence relaying a signal to the interior of the cell. ▪ Second messengers are small, non-protein, usually water-soluble molecules, or ions. They do not have enzymatic activity, but rather they act as cofactors or allosteric regulators of target enzymes. ▪ Second messengers affect many processes in the cell, thus allowing a cell to respond to a single event at the cell surface membrane with many events inside the cell. ▪ Second messengers amplify the signal because a small num