Essential Pharmacology Flashcards
Describe the basic functions of receptors.
Receptors are groups of specialised cells. They detect a change in the environment (stimulus) and stimulate electrical impulses in response.
Describe the process of transmembrane signalling.
Transmembrane signaling refers to the process by which cells communicate with each other and respond to external signals (such as hormones, neurotransmitters, or other signaling molecules) through their plasma membranes. This process is essential for regulating cellular functions, growth, differentiation, and immune responses. It involves the binding of signaling molecules (ligands) to receptors on the cell membrane, which then trigger intracellular signaling pathways to produce specific cellular responses.
Here’s a step-by-step breakdown of transmembrane signaling:
- Signal Reception
Ligand Binding: The process begins when a signaling molecule, or ligand, binds to a specific membrane receptor on the cell surface. These receptors are typically proteins that span the plasma membrane.
Types of Receptors:
G-protein-coupled receptors (GPCRs): These receptors, when activated, induce changes in the intracellular G-proteins, which in turn activate or inhibit downstream signaling pathways.
Receptor Tyrosine Kinases (RTKs): These receptors have an extracellular ligand-binding domain and an intracellular kinase domain. When ligands bind, the receptor undergoes dimerization (pairing of two receptors), activating its kinase function and leading to phosphorylation of tyrosine residues.
Ion Channel Receptors: These are channels that open in response to ligand binding, allowing ions like calcium or sodium to flow across the membrane and trigger intracellular events.
Cytokine Receptors: These receptors are involved in immune responses and typically activate intracellular signaling pathways by binding to cytokines, which lead to phosphorylation events. - Conformational Change and Signal Transduction
After ligand binding, the receptor undergoes a conformational change, which activates its intrinsic signaling capability.
GPCRs: Upon activation, GPCRs undergo a conformational change that allows them to interact with G-proteins. The G-protein exchanges GDP for GTP and dissociates into its alpha and beta-gamma subunits, each of which can interact with different intracellular signaling molecules.
RTKs: In RTKs, the conformational change typically causes the receptor to dimerize (two receptors bind together), allowing them to phosphorylate each other on specific tyrosine residues. This creates docking sites for other signaling proteins. - Intracellular Signaling Cascade
Once the receptor is activated, the signal is passed into the cell by intracellular signaling pathways. These often involve a cascade of molecular events:
Second Messengers: Small molecules like cyclic AMP (cAMP), calcium ions (Ca²⁺), or inositol trisphosphate (IP₃) are produced or released inside the cell. These molecules amplify the signal and spread it throughout the cell.
Protein Kinases: Many signaling pathways involve protein kinases (e.g., protein kinase A (PKA), protein kinase B (Akt), MAP kinases), which phosphorylate other proteins to either activate or deactivate them, altering cellular functions.
Phosphatases: These enzymes remove phosphate groups from proteins, counteracting the effects of kinases and helping to regulate the signal. - Signal Amplification
Signaling cascades often involve multiple steps where one molecule activates several others, amplifying the initial signal. For example, a single molecule of ligand can result in the activation of many G-proteins or the production of large amounts of second messengers. - Integration and Coordination of Signals
Cells often receive multiple signals simultaneously, and these signals must be integrated to generate a coherent response. Different signaling pathways can interact with each other, allowing the cell to integrate signals from different receptors and adapt to complex environments. - Cellular Response
The ultimate goal of transmembrane signaling is to produce a specific cellular response. These responses can vary widely depending on the type of receptor and the signaling pathways involved. Common responses include:
Gene Expression: Activation of transcription factors that initiate the expression of specific genes.
Metabolic Changes: Enzymes or metabolic pathways can be activated or inhibited, altering cellular metabolism.
Cell Growth and Division: Activation of cell cycle regulators that control progression through different stages of the cell cycle.
Changes in Cell Shape or Movement: Reorganization of the cytoskeleton, affecting cell motility or shape.
Apoptosis: Programmed cell death can be induced through specific signaling pathways, such as the extrinsic (death receptor) or intrinsic (mitochondrial) pathways. - Signal Termination
Deactivation: After the cellular response occurs, the signaling pathway must be turned off to prevent overactivation. This can be done by:
Degradation of Ligands: The signaling molecule is broken down or removed from the receptor.
Receptor Desensitization: The receptor may be internalized (endocytosed) or modified (e.g., phosphorylation) to reduce its responsiveness to further ligand binding.
Deactivation of Signaling Proteins: Proteins like G-proteins or kinases may be inactivated, for example by hydrolyzing GTP to GDP (in the case of G-proteins) or by dephosphorylation (in the case of kinases).
Example of Transmembrane Signaling: GPCR Pathway
Let’s consider a GPCR as an example of transmembrane signaling:
Ligand Binding: A ligand such as adrenaline binds to the beta-adrenergic receptor (a GPCR).
Conformational Change: The receptor undergoes a conformational change that activates an associated G-protein by exchanging GDP for GTP on its alpha subunit.
Signal Amplification: The activated G-protein subunits (alpha and beta-gamma) interact with other proteins or enzymes, such as adenylyl cyclase, which catalyzes the production of cAMP, a second messenger.
CAMP Activation: cAMP activates protein kinase A (PKA), which then phosphorylates target proteins to elicit a cellular response, such as increased heart rate or smooth muscle relaxation.
Termination: Phosphodiesterase breaks down cAMP, and the G-protein is deactivated by hydrolyzing GTP to GDP, halting the signaling.
Define the sources of intracellular calcium.
DETAILED: The source of calcium appears to be intracellular stores following the activation of phospholipase C (PLC) and IP3 signaling, and blocking calcium release attenuates the mechanically induced upregulation of osteogenic gene expression in vitro and abrogates load-induced bone formation in vivo.
SIMPLE: Intracellular calcium can be raised via calcium entry from the extracellular space or calcium release from the intracellular organelles.
Define what is meant by a receptor.
a cell or group of cells that receives stimuli : sense organ. 2. : a chemical group or molecule (as a protein) on the cell surface or in the cell interior that has an affinity for a specific chemical group, molecule, or virus.
Explain the terms agonist and antagonist.
An agonist is a molecule capable of binding to and functionally activating a target. The target is typically a metabotropic and/or ionotropic receptor. An antagonist is a molecule that binds to a target and prevents other molecules (e.g., agonists) from binding. Antagonists have no effect on receptor activity.
Define affinity and efficacy.
Affinity describes strength of drug binding with receptor (“fit the lock”). Efficacy describes ability of drug-bound receptor to produce a response (“turn the key”). Agonists have both affinities for the receptor as well as efficacy but antagonists have only affinity for the receptors and no (zero) efficacy.
Describe the relationship between agonist concentration and effect.
The relationship between agonist concentration and effect is typically described by a dose-response curve, which shows how the effect (or response) of a system changes as the concentration of the agonist increases. This relationship follows a characteristic pattern:
Low Concentration of Agonist: At low agonist concentrations, the effect is relatively small because only a few receptors are occupied. The system is responsive, but the effect increases slowly as more receptors are engaged.
Threshold and Linear Increase: As the agonist concentration increases, more receptors become occupied, and the effect begins to increase more rapidly. This phase often shows a near-linear relationship between concentration and response.
Emax (Maximum Effect): At a certain concentration, increasing the agonist further results in progressively smaller increases in effect. This point is where the system reaches its maximal response (Emax), and all available receptors are bound by the agonist (i.e., receptor saturation occurs).
Plateau Phase: Once the maximum effect (Emax) is reached, further increases in agonist concentration do not produce any additional effect, indicating that all receptors are fully occupied and the system is operating at maximum capacity.
Explain the therapeutic potential of selective agonists and antagonists.
Therapeutic Potential of Selective Agonists:
Targeted Treatment:
Selective agonists can activate only the desired receptor subtype, enhancing the effectiveness of the drug for a particular condition. For example, in asthma, selective agonists like beta-2 adrenergic agonists (e.g., albuterol) act on the beta-2 receptors in the lungs to cause bronchodilation without significantly affecting other parts of the body, such as the heart.
Reduced Side Effects:
By avoiding activation of other receptors that might cause side effects (such as heart rate changes, sedation, or gastrointestinal issues), selective agonists can provide more favorable side effect profiles. For example, selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels primarily in the brain, with minimal effect on other serotonin receptors that might cause side effects like gastrointestinal disturbances.
Precision Medicine:
Selective agonists allow for a more personalized approach to treatment. By understanding the receptor subtype involved in a disease process, drugs can be tailored to address that specific issue without impacting other systems in the body.
Reduced Tolerance Development:
Selective agonists may reduce the likelihood of tolerance (where increasing doses are needed for the same effect) because they target a specific pathway without overstimulating other pathways. This is especially important in chronic pain management or psychiatric conditions.
Therapeutic Potential of Selective Antagonists:
Inhibition of Overactive Receptors:
Selective antagonists can block receptors that are overactive in certain diseases. For example, beta blockers (like propranolol) block beta-adrenergic receptors, reducing heart rate and blood pressure in patients with hypertension or arrhythmias, without affecting other types of receptors involved in different systems (e.g., beta-1 receptors in the heart).
Treatment of Excessive Stimulation:
In diseases where excessive receptor activation is problematic (such as in schizophrenia, where dopamine activity is overly high), selective antagonists can reduce receptor activation specifically in certain areas of the brain. For instance, antipsychotic drugs often selectively block dopamine D2 receptors in specific brain regions to mitigate psychotic symptoms without causing broad suppression of dopamine pathways.
Blocking Harmful Effects of Endogenous Ligands:
In conditions where natural ligands (like hormones or neurotransmitters) cause harmful effects, selective antagonists can block these ligands from binding to their receptors. For example, angiotensin II receptor blockers (ARBs) inhibit the action of angiotensin II, which helps manage conditions like heart failure, where the renin-angiotensin-aldosterone system is overactive.
Potential for Reversibility:
Antagonists can sometimes have reversible effects, allowing for the restoration of normal receptor function once the antagonist is removed. This reversible blockade can be important for adjusting treatment based on the severity of the condition.
