Lecture 10 - Biochemical Signalling

Module 2: Enzymes and Cell BiologyIntroduction to Biochemical SignallingBiochemical Signalling is the cornerstone of survival in cell biology. It involves the intricate processes by which cells communicate changes in their environment and respond effectively, ensuring their functionality and viability. This signalling is essential for processes including growth, immune responses, and adaptation to stress.

Outline of Module Objectives

• Basics of Signal Transduction: Understanding how signals are transmitted across membranes, including the mechanisms of reception and transduction to ensure accurate feedback. Signal transduction encompasses the processes from signal reception to response, often leading to changes in gene expression and metabolic activity.

• Types of Signals: Different forms of chemical signals, including hormones, neurotransmitters, and local mediators, each with distinct functions such as inhibiting or promoting cellular changes. Signals can be classified as autocrine, paracrine, endocrine, or juxtacrine depending on their mode of action.

• Receptors: Key participants in signal transduction that bind to these signals. Receptors can be membrane-bound or intracellular, initiating specific cellular responses upon activation. Examples include G-Protein Coupled Receptors (GPCRs), receptor tyrosine kinases (RTKs), and ion channel receptors.

Importance of Biochemical Signalling

• Cell Communication: Necessary for cells to respond accurately to external stimuli—like the availability of nutrients or the presence of toxins—which fosters survival. Effective communication ensures that cells can coordinate their actions, particularly in multicellular organisms.

• Resource Management: Allows cells to manage internal resources efficiently, enabling them to adjust cellular activities such as metabolism, cell growth, and repair in response to internal and external cues. This regulation is vital for maintaining homeostasis within the organism.

Components of Signalling Pathways

1. Signal Release: The release of a signaling molecule in response to a specific physiological event, such as stress or nutrient availability. This can involve exocytosis of vesicles containing hormones or neurotransmitters into the extracellular space.

2. Reception: The binding of the signaling molecule (ligand) to a receptor, which triggers conformational changes that allow for the initiation of intracellular signalling cascades. The affinity and specificity of receptor-ligand interactions are crucial for effective signalling.

3. Transduction: Conversion of the signal into an intracellular response. This step often involves second messengers, such as cyclic AMP or calcium ions, which amplify the signal and facilitate a rapid cellular response.

4. Response: The resultant change in cellular activity—metabolic changes, gene expression alterations, or even changes in cell movement or connectivity. Responses are often context-dependent, based on the type of cell and the environment.

5. Switching Off: Termination of the signalling cascade is essential to prevent continuous signalling, which can lead to cell dysfunction. Deactivation mechanisms include ligand degradation, receptor endocytosis, or dephosphorylation by phosphatases.

Consequences of Signalling Cascades

• Shift in metabolic activity and gene expression can lead to various outcomes, such as cell growth, differentiation, or movement based on the combination of signals received by a cell. The integration of multiple signals allows for nuanced responses that optimize cellular function.

Hormones as Signalling MoleculesHormones are endogenous signalling molecules secreted by glands into the bloodstream, impacting target organs and tissues far from their site of production. Types of hormones include:

• Peptides: Examples include insulin (regulates glucose uptake) and glucagon (stimulates glucose release from the liver). These hormones are generally water-soluble and act via cell surface receptors.

• Steroids: Including cortisol (involved in stress response) and sex hormones (such as estrogens and androgens). They are lipid-soluble and can pass through cell membranes, acting directly on nuclear receptors to influence gene expression.

• Amino Acid Derivatives: Examples are epinephrine (a critical player in the fight-or-flight response) and thyroxine (which regulates metabolism). These molecules often have roles in both immediate and longer-term signalling processes.

Roles of Key Hormones

• Epinephrine: Involved in the "fight or flight" response, enhancing metabolic energy generation by increasing heart rate and mobilizing energy stores from fat and glycogen.

• Glucagon: Stimulates gluconeogenesis in the liver, leading to increased blood glucose levels, particularly during fasting states.

• Insulin: Promotes glucose uptake by cells, lowering blood sugar levels and enabling cells to utilize glucose for energy or store it as glycogen for future use.

Signalling Mechanisms and Receptor Types

• G-Protein Coupled Receptors (GPCRs): These receptors, upon ligand binding, activate G-proteins that relay signals to downstream effectors, initiating a cascade of responses that can affect various cellular functions.

• Enzyme-linked receptors (e.g., Receptor Tyrosine Kinases (RTKs)): Control diverse processes such as cell division and differentiation through phosphorylation events that modify the activity or function of cellular proteins.

Characteristics of RTKsRTKs possess an extracellular ligand-binding domain, a single transmembrane domain, and intrinsic intracellular tyrosine kinase activity. Binding of a ligand leads to receptor dimerization, autophosphorylation, and the activation of multiple downstream signalling pathways that regulate key cellular functions.

Activation and Functionality of RTKs

• Adaptor Proteins: Contain SH2/SH3 domains that link RTKs to other signalling proteins, amplifying the signal and ensuring specificity of the response. These proteins act as molecular scaffolds, organizing signalling complexes and facilitating efficient signal transduction.

• Deactivation: Involves protein phosphatases that remove phosphate groups from the activated proteins, thereby halting the signalling pathway and resetting the cellular environment for subsequent signalling events.

Cancer and RTKsCertain cancers, such as Chronic Myelogenous Leukemia (CML), feature aberrant RTK signalling. The dysregulation of these pathways can lead to uncontrolled cell proliferation and survival.

• Drugs like Gleevec inhibit the abnormal activity of specific RTKs, providing effective therapeutic strategies for treating cancers by disrupting faulty signalling pathways that drive tumor growth.

Summary of RTK SignallingDimerization and phosphorylation in RTKs are crucial for signal transduction, and these processes play significant roles in regulating physiological responses. Dysregulated RTK signalling can lead to growth and metabolism advantages in pathological conditions, highlighting the importance of understanding these pathways for developing targeted therapies against cancers and other diseases.