<img/> THE UNIVERSITY OF WESTERN AUSTRALIA DENT 3005:Introduction to Pharmacology **Pharmacodynamics** Dr Thuy Linh Truong thuy.truong@uwa.edu.au Acknowledgement: Sheetal Maria Rajan ## **Acknowledgement of country** The University of Western Australia acknowledges that its campus is situated on Noongar land, and that Noongar people remain the spiritual and cultural custodians of their land, and continue to practise their values, languages, beliefs and knowledge. **Artist:** Dr Richard Barry Walley OAM <img > </img> **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** Acknowledgement of country The University of Western Australia acknowledges that its campus is situated on Noongar land, and that Noongar people remain the spiritual and cultural custodians of their land, and continue to practise their values, languages, beliefs and knowledge. Artist: Dr Richard Barry Walley OAM **DENT3005: assessment breakdown** | Assessment # | Assessment Task | Weight % | Assessment Period/ date | Module assessed | Waiver | |---|---|---|---|---|---| | 1 | SAQ | 50% | 30/09/25 9AM – 11AM | General Medicine and Pharmacology: all lectures content | No | | 2 | MCQ | 50% | Main Campus: Semester 2 examination period | General Medicine and Pharmacology: all lectures content | No | # **DENT3005: assessment breakdown** | Assessment # | Assessment Task | Weight % | Assessment Period/ date | Module assessed | Waiver | |---|---|---|---|---|---| | 1 | SAQ | 50% | 30/09/25 9AM – 11AM | General Medicine and Pharmacology: all lectures content | No | | 2 | MCQ | 50% | Main Campus: Semester 2 examination period | General Medicine and Pharmacology: all lectures content | No | Learning outcomes Broad * Explain the principles of drug delivery, drug metabolism, and associated pharmacological aspects as they relate to dental practice * Define the terms receptor, drug agonist, and drug antagonist * Describe the different types of receptor and pharmacodynamic factors influencing drug-receptor interactions **Specific topics we will cover:** * Receptors * **Drug-induced responses** * Receptor agonist and antagonist * **Possible drug targets** * Four main drug receptors: Ion channels, G protein-coupled receptors, kinase-linked receptors, nuclear receptors Illustration showing a person receiving medication, medicine bottles, and a diagram illustrating pharmacodynamics with agonist, antagonist, and partial agonist interactions. # **Learning outcomes** ## **Broad** - Explain the principles of drug delivery, drug metabolism, and associated pharmacological aspects as they relate to dental practice - Define the terms receptor, drug agonist, and drug antagonist - Describe the different types of receptor and pharmacodynamic factors influencing drug-receptor interactions ## **Specific topics we will cover:** - Receptors - **Drug-induced responses** - Receptor agonist and antagonist - **Possible drug targets** - Four main drug receptors: Ion channels, G protein-coupled receptors, kinase-linked receptors, nuclear receptors **Pharmacodynamics vs. Pharmacokinetics** | Pharmacodynamics | Pharmacokinetics | |---|---| | **Pharmacodynamics** = What the **DRUG** does to the **BODY** | **Pharmacokinetics** = What the **BODY** does to the **DRUG** | <img alt="Diagram showing Pharmacodynamics as the effect of a Dose resulting in Activity through Mechanisms, and Pharmacokinetics as the ADME process (Absorption, Distribution, Metabolism in the Liver, and Excretion)." /> **Pharmacodynamics** * Pharmacodynamics * Dose * Mechanisms * Activity **Pharmacokinetics** The principles of ADME * Medicine * Absorption: How will it get in? * Distribution: Where will it go? * Transporters * Metabolism: How is it broken down? * Liver * Excretion: How does it leave? * EUPATI * European Patients' Academy * on Therapeutic Innovation * www.eupati.eu # **Pharmacodynamics vs. Pharmacokinetics** | Pharmacodynamics | Pharmacokinetics | |---|---| | **Pharmacodynamics** = What the **DRUG** does to the **BODY** | **Pharmacokinetics** = What the **BODY** does to the **DRUG** | # Pharmacodynamics * **Mechanism whereby drug exert their effect on body → therapeutic response** * **Usually acting on physiological processes** * **Aim of drug therapy: reverse changes → homeostasis** * **Modification of processes** * **Examples** * **Hypertension: antihypertensives** <img src='Description: Diagram showing a relationship between drug dose, mechanisms of action within the body, and resulting activity (therapeutic response) in pharmacodynamics.'> </img> Key terms * Receptor * Affinity * Agonism * Antagonism * Competitive and noncompetitive enzyme inhibition * Efficacy * Potency * Receptors * Specificity <img alt="information icon" /> # **Key terms** - Receptor - Affinity - Agonism - Antagonism - Competitive and noncompetitive enzyme inhibition - Efficacy - Potency - Receptors - Specificity * What is a drug? * A chemical $\rightarrow$ produce biological effect * How are drugs classified? * Chemical structure * Mechanism of action- *how does it work?* * Therapeutic use – *what is it designed to do?* * Drug nomenclature * Chemical name * Eg. 7,8-didehydro-4,5a-epoxy-17- methylmorphinan-3,6a-diol sulfate!!!!! * Generic name * Eg. Morphine sulfate * Brand name * Eg. Kapanol, Ms Contin, Ms Mono... ## **What is a drug?** - A chemical $\rightarrow$ produce biological effect ## **How are drugs classified?** - Chemical structure - Mechanism of action- *how does it work?* - Therapeutic use – *what is it designed to do?* ## **Drug nomenclature** - **Chemical name** - Eg. 7,8-didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-diol sulfate!!!!! - **Generic name** - Eg. Morphine sulfate - **Brand name** - Eg. Kapanol, Ms Contin, Ms Mono... - **Basic principle** - Drug molecule exerting chemical influence $\rightarrow$ pharmacological response - Non-uniform distribution - Drug must be bound to a critical binding site "target" - **Protein targets** - Receptors - Enzymes - Carrier molecules (transporters) - Ion channels - **How drugs function?** - Agonist - Antagonist - Inverse agonist - Toxicity? ## **Basic principle** - Drug molecule exerting chemical influence $\rightarrow$ pharmacological response - Non-uniform distribution - Drug must be bound to a critical binding site "target" ## **Protein targets** - Receptors - Enzymes - Carrier molecules (transporters) - Ion channels ## **How drugs function?** - Agonist - Antagonist - Inverse agonist - Toxicity? * **What is a receptor?** * Specialized proteins * On cell surfaces/within cells * Transmit signals in the body * **Importance** * Key players in mediating the effects of drugs * Cellular communication * **Binding:** ligand-receptor interaction * **Signal transduction** – ligand binding triggering cellular changes Diagram illustrating ligand-receptor binding and mechanisms of action for agonists, inverse agonists, and antagonists. It shows the binding site, the initial binding of a ligand, and the downstream effects for different types of drugs (Direct effects, Transduction mechanisms, No effect). ## **What is a receptor?** - Specialized proteins - On cell surfaces/within cells - Transmit signals in the body ### **Importance** - Key players in mediating the effects of drugs - Cellular communication ### **Binding** - ligand-receptor interaction ### **Signal transduction** - ligand binding triggering cellular changes **Drug-receptor interactions:** o Chemical structure o Molecular size and shape o Lipophilicity o pH & lonization **Drug binding & receptor activation** o Affinity o Efficacy A diagram illustrating a drug being administered to a person and then a zoomed-in illustration showing a ligand interacting with a binding site. ## **Drug-receptor interactions:** - Chemical structure - Molecular size and shape - Lipophilicity - pH & lonization ## **Drug binding & receptor activation** - Affinity - Efficacy # Drug-Receptor Binding Affinity: Tendency of a drug to bind to a receptor * $\uparrow$ Affinity = Greater binding tendency * Measured by **Kd (Equilibrium dissociation constant, mol/L)** * Lower Kd = Higher affinity Efficacy: Ability of a drug to produce an effect at the receptor * $\uparrow$ Efficacy = Greater maximum effect * More efficacious drug = Greater effect, not necessarily stronger binding **Agonist**: Has both **affinity** and **efficacy** **Antagonist**: Has **affinity**, but **no efficacy** $$[D] + [R] \underset{k_{-1}}{\stackrel{k_1}{\rightleftharpoons}} [DR]$$ **Reversible reaction** * k$\_1$ & k$\_{-1}$ are the rate constants for association and dissociation $$K_D = \frac{k_{-1}}{k_1}$$ **Drugs with $\downarrow$Low Kd = $\uparrow$Affinity** **Drugs with $\uparrow$ High Kd = $\downarrow$ Affinity** <br> <img src="diagram_drug_receptor_binding.png" alt="Diagram showing the reversible reaction of a drug [D] binding to a receptor [R] to form a drug-receptor complex [DR], with rate constants $k_1$ for association and $k_{-1}$ for dissociation, and the equation for the equilibrium dissociation constant: $K_D = k_{-1} / k_1$." /> Drug-Receptor interactions, EKG Science # **Drug-Receptor Binding** ## **Affinity** Tendency of a drug to bind to a receptor - $\uparrow$ Affinity = Greater binding tendency - Measured by **Kd (Equilibrium dissociation constant, mol/L)** - Lower Kd = Higher affinity ## **Efficacy** Ability of a drug to produce an effect at the receptor - $\uparrow$ Efficacy = Greater maximum effect - More efficacious drug = Greater effect, not necessarily stronger binding - **Agonist**: Has both **affinity** and **efficacy** - **Antagonist**: Has **affinity**, but **no efficacy** $$[D] + [R] \underset{k_{-1}}{\stackrel{k_1}{\rightleftharpoons}} [DR]$$ **Reversible reaction** - k$\_1$ & k$\_{-1}$ are the rate constants for association and dissociation $$K_D = \frac{k_{-1}}{k_1}$$ - **Drugs with $\downarrow$Low Kd = $\uparrow$Affinity** - **Drugs with $\uparrow$ High Kd = $\downarrow$ Affinity** <br> Drug-Receptor interactions, EKG Science # Drug-Receptor Binding **Potency:** (the relative amount of drug that has to be present to produce an effect) * **EC$_{50}$** –the concentration at which **50% of the max response (to the drug) is observed** * **$\uparrow$EC$_{50}$: more drug req = lower potency** **Specificity:** (relates to degree of selectivity) * **$\uparrow$Specificity: targeted action, lowered side-effects** Fundamentals of Pharmacology Two dose-response curves comparing Drug X and Drug Y for potency and efficacy in two different hypothetical scenarios. # **Drug-Receptor Binding** ## **Potency** (the relative amount of drug that has to be present to produce an effect) - **EC$_{50}$** –the concentration at which **50% of the max response (to the drug) is observed** - **$\uparrow$EC$_{50}$: more drug req = lower potency** ## **Specificity** (relates to degree of selectivity) - **$\uparrow$Specificity: targeted action, lowered side-effects** Fundamentals of Pharmacology **Drug-Receptor Binding** **Agonist** An agonist is a drug that binds to and activates a receptor **Partial agonist** – can bind to and activate the receptor - Lower efficacy – cannot produce the same maximum effect as a full agonist **Antagonist** An antagonist is a drug that binds to the receptor & does NOT cause activation - **Competitive antagonist**: reversible/ surmountable - **Non-competitive antagonist**: irreversible/ insurmountable - **Physiological antagonism**: 2 drugs have effects that are functionally the opposite | | | :---: | | **RECAP Efficacy: The** | | ability of the agonist- | | receptor complex to initiate | | changes that induce a | | response | Drug-Receptor interactions, EKG Science ```mermaid flowchart TD subgraph Drug A Binding and Effect A["Drug A (agonist)"] --> B(R) B -- Affinity, k1 --> C(AR) B -- k-1 --> A C -- Efficacy, β --> D(AR*) C -- α --> B D --> E[Response] end subgraph Agonist Action Agonist[Agonist] --> Receptor1(Receptor) Receptor1 --> F[Full activation & Response] end ``` ```mermaid flowchart TD subgraph Drug B Binding and Effect G["Drug B (antagonist)"] --> H(R) H -- Affinity, k1 --> I(BR) H -- k-1 --> G I --> J[No Response] end subgraph Antagonist Action Antagonist[Antagonist] --> Receptor2(Receptor) Receptor2 --> K[No activation & response] end ``` # **Drug-Receptor Binding** ## **Agonist** An agonist is a drug that binds to and activates a receptor ### **Partial agonist** - can bind to and activate the receptor - Lower efficacy – cannot produce the same maximum effect as a full agonist ## **Antagonist** An antagonist is a drug that binds to the receptor & does NOT cause activation - **Competitive antagonist**: reversible/ surmountable - **Non-competitive antagonist**: irreversible/ insurmountable - **Physiological antagonism**: 2 drugs have effects that are functionally the opposite > **RECAP Efficacy: The** > ability of the agonist- > receptor complex to initiate > changes that induce a > response Drug-Receptor interactions, EKG Science ```mermaid flowchart TD subgraph Drug A Binding and Effect A["Drug A (agonist)"] --> B(R) B -- Affinity, k1 --> C(AR) B -- k-1 --> A C -- Efficacy, β --> D(AR*) C -- α --> B D --> E[Response] end subgraph Agonist Action Agonist[Agonist] --> Receptor1(Receptor) Receptor1 --> F[Full activation & Response] end ``` ```mermaid flowchart TD subgraph Drug B Binding and Effect G["Drug B (antagonist)"] --> H(R) H -- Affinity, k1 --> I(BR) H -- k-1 --> G I --> J[No Response] end subgraph Antagonist Action Antagonist[Antagonist] --> Receptor2(Receptor) Receptor2 --> K[No activation & response] end ``` **Inverse Agonist** - **Inverse agonist are special** - Pharmacological agonist - Decrease level of receptor activation - Negative efficacy - NOT an antagonist - Do not cause activation (zero efficacy) <img src='pharmacologic_agonists_diagram.png'> **Pharmacologic Agonists** | Drug | Receptor | Effect | | :---: | :---: | :---: | | Full agonist | <img src='full_agonist_receptor_binding.png'> | <img src='full_agonist_effect.png'> | | Partial agonist | <img src='partial_agonist_receptor_binding.png'> | <img src='partial_agonist_effect.png'> | | Inverse agonist | <img src='inverse_agonist_receptor_binding.png'> | <img src='inverse_agonist_effect.png'> | <img src='dose_response_curve.png'> ## **Inverse Agonist** - **Inverse agonist are special** - Pharmacological agonist - Decrease level of receptor activation - Negative efficacy - NOT an antagonist - Do not cause activation (zero efficacy) ### **Pharmacologic Agonists** | Drug | Receptor | Effect | | :---: | :---: | :---: | | Full agonist | | | | Partial agonist | | | | Inverse agonist | | | # Drug-Receptor Binding **C**oncentration-response **curves (CRC)**: Tool for understanding the connection between a drug and its biological effects **Agonists** Emax – is the maximum response that can be achieved by the drug under the given conditions EC50 – is the drug concentration at which **50% of the maximum response (to the drug) is observed** EC50 provides a measure of **drug potency** **RECAP Potency**: measure of drug activity/ amount of drug that is required to produce a particular effect * Lower EC50 = **Higher potency** * Low potency – requires a higher concentration ## Concentration-Response Curve Diagram The image displays a graph illustrating a concentration-response curve (CRC) and associated concepts. **Y-axis:** % response (from 0 to 100) **X-axis:** \[Agonist\] (M) (from $10^{-12}$ to $10^{-2}$) **Key labels on the graph:** * Emax * Increased risk of adverse reactions * Therapeutic range * EC50 * Sub-therapeutic effect --- Drug-Receptor interactions, EKG Science A graph showing the relationship between agonist concentration (log scale) and percent response, illustrating Emax, EC50, therapeutic range, increased risk of adverse reactions, and sub-therapeutic effect. # **Drug-Receptor Binding** ## **Concentration-response curves (CRC)** Tool for understanding the connection between a drug and its biological effects ### **Agonists** - **Emax** – is the maximum response that can be achieved by the drug under the given conditions - **EC50** – is the drug concentration at which **50% of the maximum response (to the drug) is observed** - **EC50** provides a measure of **drug potency** > **RECAP Potency**: measure of drug activity/ amount of drug that is required to produce a particular effect - Lower EC50 = **Higher potency** - Low potency – requires a higher concentration ### **Concentration-Response Curve Diagram** The image displays a graph illustrating a concentration-response curve (CRC) and associated concepts. - **Y-axis:** % response (from 0 to 100) - **X-axis:** \[Agonist\] (M) (from $10^{-12}$ to $10^{-2}$) **Key labels on the graph:** - Emax - Increased risk of adverse reactions - Therapeutic range - EC50 - Sub-therapeutic effect --- Drug-Receptor interactions, EKG Science **Drug-Receptor Binding** **Concentration-response curves (CRC) for Antagonists** **Competitive Antagonist** * Agonist and antagonist compete for the same Orthosteric site * Surmountable – increasing the con. of the agonist can overcome the binding of the competitive antagonist * Increasing con. of a competitive antagonist will cause a parallel rightward shift in the agonist CRC *** **Non-competitive antagonist** * Insurmountable – antagonist drug reduces the maximum effect of the agonist * Irreversibly alters the target receptors (e.g. forming covalent bonds) * High affinity for the receptor- dissociates slowly. * Maximum response cannot be achieved *** Lambert DG. (2004). Drugs and receptors. Continuing Education in Anaesthesia Critical Care & Pain; 4(6):181–184. Concentration-response curve showing the effects of a competitive and a non-competitive antagonist on an agonist response. # **Drug-Receptor Binding** ## **Concentration-response curves (CRC) for Antagonists** ### **Competitive Antagonist** - Agonist and antagonist compete for the same Orthosteric site - Surmountable – increasing the con. of the agonist can overcome the binding of the competitive antagonist - Increasing con. of a competitive antagonist will cause a parallel rightward shift in the agonist CRC *** ### **Non-competitive antagonist** - Insurmountable – antagonist drug reduces the maximum effect of the agonist - Irreversibly alters the target receptors (e.g. forming covalent bonds) - High affinity for the receptor- dissociates slowly. - Maximum response cannot be achieved *** Lambert DG. (2004). Drugs and receptors. Continuing Education in Anaesthesia Critical Care & Pain; 4(6):181–184. Slide with the word "Review!" centered on a blue gradient background Other considerations * Drugs that work by simple chemical or physical action * Neutralization of acidic environment * Chelating * Osmosis # **Other considerations** - Drugs that work by simple chemical or physical action - Neutralization of acidic environment - Chelating - Osmosis **Protein Targets for Drug Action** ***mermaid*** flowchart TD subgraph A RECEPTORS A1(Agonist/inverse agonist) -->|Direct| A1.1(lon channel opening/closing) A1 -->|Transduction mechanisms| A1.2(Enzyme activation/inhibition) A1 -->|Transduction mechanisms| A1.3(lon channel modulation) A1 -->|Transduction mechanisms| A1.4(DNA transcription) A2(Antagonist) --> A2.1(No effect Endogenous mediators blocked) end subgraph B ION CHANNELS B1(Blockers) --> B1.1(Permeation blocked) B2(Modulators) --> B2.1(Increased or decreased opening probability) end subgraph C ENZYMES C1(Inhibitor) --> C1.1(Normal reaction inhibited) C2(False substrate) --> C2.1(Abnormal metabolite produced) C3(Prodrug) --> C3.1(Active drug produced) end subgraph D TRANSPORTERS D1(Normal transport) --> D1.1(Transported compound) D2(Inhibitor) --> D2.1(Transport blocked) D3(False substrate) --> D3.1(Abnormal compound accumulated) end *** <style> .legend-item { display: flex; align-items: center; margin-right: 10px; } .dot { height: 10px; width: 10px; border-radius: 50%; display: inline-block; margin-right: 5px; } .pink-dot { background-color: #ff69b4; } .black-dot { background-color: black; } .red-dot { background-color: red; } .cyan-dot { background-color: cyan; } </style> <div style="display: flex;"> <div class="legend-item"> <span class="dot pink-dot"></span> Agonist/substrate </div> <div class="legend-item"> <span class="dot black-dot"></span> Antagonist/inhibitor </div> <div class="legend-item"> <span class="dot red-dot"></span> Abnormal product </div> <div class="legend-item"> <span class="dot cyan-dot"></span> Prodrug </div> </div> *Rang & Dale’s Pharmacology, Tenth Edition* # **Protein Targets for Drug Action** ***mermaid*** flowchart TD subgraph A RECEPTORS A1(Agonist/inverse agonist) -->|Direct| A1.1(lon channel opening/closing) A1 -->|Transduction mechanisms| A1.2(Enzyme activation/inhibition) A1 -->|Transduction mechanisms| A1.3(lon channel modulation) A1 -->|Transduction mechanisms| A1.4(DNA transcription) A2(Antagonist) --> A2.1(No effect Endogenous mediators blocked) end subgraph B ION CHANNELS B1(Blockers) --> B1.1(Permeation blocked) B2(Modulators) --> B2.1(Increased or decreased opening probability) end subgraph C ENZYMES C1(Inhibitor) --> C1.1(Normal reaction inhibited) C2(False substrate) --> C2.1(Abnormal metabolite produced) C3(Prodrug) --> C3.1(Active drug produced) end subgraph D TRANSPORTERS D1(Normal transport) --> D1.1(Transported compound) D2(Inhibitor) --> D2.1(Transport blocked) D3(False substrate) --> D3.1(Abnormal compound accumulated) end *** <style> .legend-item { display: flex; align-items: center; margin-right: 10px; } .dot { height: 10px; width: 10px; border-radius: 50%; display: inline-block; margin-right: 5px; } .pink-dot { background-color: #ff69b4; } .black-dot { background-color: black; } .red-dot { background-color: red; } .cyan-dot { background-color: cyan; } </style> <div style="display: flex;"> <div class="legend-item"> <span class="dot pink-dot"></span> Agonist/substrate </div> <div class="legend-item"> <span class="dot black-dot"></span> Antagonist/inhibitor </div> <div class="legend-item"> <span class="dot red-dot"></span> Abnormal product </div> <div class="legend-item"> <span class="dot cyan-dot"></span> Prodrug </div> </div> *Rang & Dale’s Pharmacology, Tenth Edition* **Types of Receptors** **Receptor:** Specialized proteins located on cell surfaces/within cells that are responsible for transmitting signals in the body | 1. Ligand-gated ion channels (ionotropic receptors) | 2. G protein-coupled receptors (metabotropic) | 3. Kinase-linked receptors | 4. Nuclear receptors | |---|---|---|---| ```mermaid graph TD A[Ions] --> B{Hyperpolarisation or depolarisation}; A --> C{Change in excitability}; C --> D[Ca²⁺ release]; R(R) --> E{Second messengers} E --> F[Protein phosphorylation]; E --> G[Other]; R/E(R/E) --> H[Protein phosphorylation]; H --> I[Gene transcription]; I --> J[Protein synthesis]; N(NUCLEUS: R) --> K[Gene transcription]; K --> L[Protein synthesis]; B --> M[Cellular effects]; D --> M; F --> M; G --> M; J --> M; L --> M; subgraph Time Scale style Time Scale fill:#f0f0f0 Mmillisecond[Milliseconds] Ssecond[Seconds] Hhour[Hours] H2hour[Hours] end subgraph Examples style Examples fill:#f0f0f0 N(Nicotinic ACh receptor) M2(Muscarinic ACh receptor) C(Cytokine receptors) O(Oestrogen receptor) end Mmillisecond --> N Ssecond --> M2 Hhour --> C H2hour --> O ``` <ins>**Time scale**</ins> | Milliseconds | Seconds | Hours | Hours | |---|---|---|---| | **Examples** | Muscarinic ACh receptor | Cytokine receptors | Oestrogen receptor | | Nicotinic ACh receptor | | | | Rang & Dale's Pharmacology, Tenth Edition # **Types of Receptors** **Receptor:** Specialized proteins located on cell surfaces/within cells that are responsible for transmitting signals in the body | 1. Ligand-gated ion channels (ionotropic receptors) | 2. G protein-coupled receptors (metabotropic) | 3. Kinase-linked receptors | 4. Nuclear receptors | |---|---|---|---| ```mermaid graph TD A[Ions] --> B{Hyperpolarisation or depolarisation}; A --> C{Change in excitability}; C --> D[Ca²⁺ release]; R(R) --> E{Second messengers} E --> F[Protein phosphorylation]; E --> G[Other]; R/E(R/E) --> H[Protein phosphorylation]; H --> I[Gene transcription]; I --> J[Protein synthesis]; N(NUCLEUS: R) --> K[Gene transcription]; K --> L[Protein synthesis]; B --> M[Cellular effects]; D --> M; F --> M; G --> M; J --> M; L --> M; subgraph Time Scale style Time Scale fill:#f0f0f0 Mmillisecond[Milliseconds] Ssecond[Seconds] Hhour[Hours] H2hour[Hours] end subgraph Examples style Examples fill:#f0f0f0 N(Nicotinic ACh receptor) M2(Muscarinic ACh receptor) C(Cytokine receptors) O(Oestrogen receptor) end Mmillisecond --> N Ssecond --> M2 Hhour --> C H2hour --> O ``` <ins>**Time scale**</ins> | Milliseconds | Seconds | Hours | Hours | |---|---|---|---| | **Examples** | Muscarinic ACh receptor | Cytokine receptors | Oestrogen receptor | | Nicotinic ACh receptor | | | | Rang & Dale's Pharmacology, Tenth Edition **Types of Receptors: in a nutshell!** | | **Type 1: Ligand gated ion channels** | **Type 2: G-Protein coupled receptors** | **Type 3: Receptor kinases** | **Type 4: Nuclear receptors** | | :--- | :--- | :--- | :--- | :--- | | **Location** | Membrane | Membrane | Membrane | Intracellular | | **Effector** | Ion Channel | Channel or enzyme | Protein Kinases | Genes Transcription | | **Coupling** | Direct | G Protein or arrestin | Direct | Via DNA | | **Examples** | Nicotinic acetylcholine receptor, GABAA receptor | Muscarinic acetylcholine receptors, adrenoceptors | Insulin, growth factors, cytokine receptors | Steroid receptors | | **Structure** | Oligomeric assembly of subunits surround central pore | Monomeric/oligomeric assembly of subunits: 7 transmembrane helices with intracellular G-Protein coupling domain | Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain | Monomeric structure with receptor and DNA binding domains | Rang & Dale’s Pharmacology, Tenth Edition # **Types of Receptors: in a nutshell!** | | **Type 1: Ligand gated ion channels** | **Type 2: G-Protein coupled receptors** | **Type 3: Receptor kinases** | **Type 4: Nuclear receptors** | | :--- | :--- | :--- | :--- | :--- | | **Location** | Membrane | Membrane | Membrane | Intracellular | | **Effector** | Ion Channel | Channel or enzyme | Protein Kinases | Genes Transcription | | **Coupling** | Direct | G Protein or arrestin | Direct | Via DNA | | **Examples** | Nicotinic acetylcholine receptor, GABAA receptor | Muscarinic acetylcholine receptors, adrenoceptors | Insulin, growth factors, cytokine receptors | Steroid receptors | | **Structure** | Oligomeric assembly of subunits surround central pore | Monomeric/oligomeric assembly of subunits: 7 transmembrane helices with intracellular G-Protein coupling domain | Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain | Monomeric structure with receptor and DNA binding domains | Rang & Dale’s Pharmacology, Tenth Edition **Type 1: Ligand-gated Ion Channel receptors** * **Ionotropic** * **Neurotransmitters** * **Timescale:** milliseconds * **Localization:** membrane * **Effector:** ion channel * **Coupling:** direct **Ion channels are characterized by** 1. Selectivity for particular ion species * Size of the pore and nature of its lining * Cations: ${Na}^{+}$, ${Ca}^{2+}$, ${K}^{+}$ * Anions: ${Cl}^{-}$ 2. Gating properties * Control transition from open to closed states 3. Molecular structure **4-5 subunits** **Examples** * **Nicotinic Ach Receptor** * **GABA A Receptor** * **Glutamate Receptor** * **Glycine Receptor** Types of receptors, EKG Science # **Type 1: Ligand-gated Ion Channel receptors** - **Ionotropic** - **Neurotransmitters** - **Timescale:** milliseconds - **Localization:** membrane - **Effector:** ion channel - **Coupling:** direct ## **Ion channels are characterized by** 1. **Selectivity for particular ion species** - Size of the pore and nature of its lining - Cations: ${Na}^{+}$, ${Ca}^{2+}$, ${K}^{+}$ - Anions: ${Cl}^{-}$ 2. **Gating properties** - Control transition from open to closed states 3. **Molecular structure** **4-5 subunits** ## **Examples** - **Nicotinic Ach Receptor** - **GABA A Receptor** - **Glutamate Receptor** - **Glycine Receptor** Types of receptors, EKG Science **Example: Nicotinic Acetylcholine Receptor** **Nicotine** Outside of cell Cell membrane Inside of cell **GABA** Outside of cell Cell membrane Inside of cell <img src="nicotinic_acetylcholine_receptor.jpg" alt="Diagram illustrating the structure and function of the Nicotinic Acetylcholine Receptor (nAChR) and the GABAA receptor. The nAChR structure shows subunits ($\alpha$, $\beta$, $\gamma$, $\delta$, and $\epsilon$ in the pentameric view, and $\alpha$, $\beta$, $\delta$, $\alpha$ in the cross-section view on the left) forming a gate, with AcH binding sites. The pore size is indicated as ~0.7 nm. The functional diagrams show Nicotine binding to nAChR causing the channel to open and allow $Na^+$ ions to flow in, and GABA binding to the **GABA** receptor causing the channel to open and allow $Cl^-$ and $K^+$ ions to flow in and out respectively."> | Element | Description | |---|---| | ACH (ACh) | Acetylcholine binding site | | $\alpha$, $\beta$, $\delta$, $\gamma$ | Receptor subunits | | a-Helices forming gate | Structure controlling channel opening | | Pore (~0.7 nm) | The opening for ion passage | | Closed channel | Receptor state without ligand binding | | Open channel | Receptor state after ligand binding (Nicotine or GABA) | | $Na^+$ | Sodium ion flow through nAChR | | $Cl^-$, $K^+$ | Chloride and Potassium ion flow through GABA receptor | ## **Example: Nicotinic Acetylcholine Receptor** **Nicotine** - Outside of cell - Cell membrane - Inside of cell **GABA** - Outside of cell - Cell membrane - Inside of cell | Element | Description | |---|---| | ACH (ACh) | Acetylcholine binding site | | $\alpha$, $\beta$, $\delta$, $\gamma$ | Receptor subunits | | a-Helices forming gate | Structure controlling channel opening | | Pore (~0.7 nm) | The opening for ion passage | | Closed channel | Receptor state without ligand binding | | Open channel | Receptor state after ligand binding (Nicotine or GABA) | | $Na^+$ | Sodium ion flow through nAChR | | $Cl^-$, $K^+$ | Chloride and Potassium ion flow through GABA receptor | Slide with the text "Review!" centered on a gradient blue background **Type 2: G-protein coupled receptors** * Metabotropic * Largest family * Timescale: seconds * Location: membrane * Effector: channel or enzyme * Coupling: G-Protein **Function** * Recognise and activate GPCRs $\to$ pass message to effector system $\to$ generate cellular response * Signal amplification * Four main classes Binding domains Outside of cell Cell membrane Inside of cell G-protein coupling domain **Examples** **Adrenoceptors** **Muscarinic Ach** **Histamine** **Serotonin** **Opioid** # **Type 2: G-protein coupled receptors** - Metabotropic - Largest family - Timescale: seconds - Location: membrane - Effector: channel or enzyme - Coupling: G-Protein ## **Function** - Recognise and activate GPCRs $\to$ pass message to effector system $\to$ generate cellular response - Signal amplification - Four main classes ### **Binding domains** - Outside of cell - Cell membrane - Inside of cell ### **G-protein coupling domain** ## **Examples** - **Adrenoceptors** - **Muscarinic Ach** - **Histamine** - **Serotonin** - **Opioid** Series of labeled diagrams illustrating a G-protein coupled receptor (GPCR) signaling pathway with steps involving signaling molecules, receptor activation, G-protein subunit interactions, and activation of target proteins. **Example: cyclic AMP pathways** * G-protein coupling domain comprises of 3 subunits ($\alpha$,$\beta$,$\gamma$) * G$\alpha$ proteins link GPCRs to effector proteins that generate intracellular second messengers * G$\alpha$s - Activates adenylate cyclase- Generates cAMP * G$\alpha$i- Inhibits adenylate cyclase * G$\alpha$q - Activates phospholipase C- Generates inositol triphosphate and diacylglycerol **Adenylate cyclase signal transduction pathway** 1. GTP binds to G$\alpha$ $\rightarrow$ Activation of G protein 2. G$\alpha$ dissociates from G$\beta$$\gamma$ $\rightarrow$ Binds to adenylate cyclase $\rightarrow$ activation of cAMP 3. G$\alpha$ dissociates from adenylate cyclase $\&$ binds to G$\beta$$\gamma$ $\rightarrow$ inactivation of cAMP 4. Returning to G state ```mermaid graph TD A[Agonist] --> B(GPCR); B --> C{GTP}; C --> D[Gα]; C --> E[Gαs]; C --> F[Gαi]; C --> G[Gαq]; D --> H[Gβγ]; B --> H; E --> I[AC]; F -.- I; % Inhibitory link shown by dashed line/red arrow in original figure/image I --> J[ATP]; J --> K[cAMP]; K --> L[PKA]; G --> M[PLC]; H --> N[Ion channel]; N --> O(Ions); M --> P[PIP2]; P --> Q[DAG]; P --> R[IP3]; Q --> S[PKC]; R --> T[Ca2+ from ER lumen]; S --> U[Ca2+]; T --> U; D --> V[Gα 12/13]; V --> W[RhoGEF]; W --> X[RhoA]; style E fill:#4CAF50,stroke:#333 style F fill:#4CAF50,stroke:#333 style G fill:#4CAF50,stroke:#333 style V fill:#4CAF50,stroke:#333 style I fill:#FFCC80,stroke:#333 style M fill:#4D8EDD,stroke:#333 style L fill:#FF4D4D,stroke:#333 style S fill:#FF4D4D,stroke:#333 style W fill:#AAAAAA,stroke:#333 style X fill:#AAAAAA,stroke:#333 style Q fill:#FFCC80,stroke:#333 style R fill:#FFCC80,stroke:#333 style K fill:#FF4D4D,stroke:#333 style N fill:#FFCC80,stroke:#333 ``` Chen Y, Palczewski K. (2016). Systems Pharmacology Links GPCRs with Retinal Degenerative Disorders. Annu Rev Pharmacol Toxicol;56:273-98.Rang & Dale's Pharmacology, Ninth Edition ## **Example: cyclic AMP pathways** - G-protein coupling domain comprises of 3 subunits ($\alpha$,$\beta$,$\gamma$) - G$\alpha$ proteins link GPCRs to effector proteins that generate intracellular second messengers - G$\alpha$s - Activates adenylate cyclase- Generates cAMP - G$\alpha$i- Inhibits adenylate cyclase - G$\alpha$q - Activates phospholipase C- Generates inositol triphosphate and diacylglycerol ### **Adenylate cyclase signal transduction pathway** 1. GTP binds to G$\alpha$ $\rightarrow$ Activation of G protein 2. G$\alpha$ dissociates from G$\beta$$\gamma$ $\rightarrow$ Binds to adenylate cyclase $\rightarrow$ activation of cAMP 3. G$\alpha$ dissociates from adenylate cyclase $\&$ binds to G$\beta$$\gamma$ $\rightarrow$ inactivation of cAMP 4. Returning to G state ```mermaid graph TD A[Agonist] --> B(GPCR); B --> C{GTP}; C --> D[Gα]; C --> E[Gαs]; C --> F[Gαi]; C --> G[Gαq]; D --> H[Gβγ]; B --> H; E --> I[AC]; F -.- I; % Inhibitory link shown by dashed line/red arrow in original figure/image I --> J[ATP]; J --> K[cAMP]; K --> L[PKA]; G --> M[PLC]; H --> N[Ion channel]; N --> O(Ions); M --> P[PIP2]; P --> Q[DAG]; P --> R[IP3]; Q --> S[PKC]; R --> T[Ca2+ from ER lumen]; S --> U[Ca2+]; T --> U; D --> V[Gα 12/13]; V --> W[RhoGEF]; W --> X[RhoA]; style E fill:#4CAF50,stroke:#333 style F fill:#4CAF50,stroke:#333 style G fill:#4CAF50,stroke:#333 style V fill:#4CAF50,stroke:#333 style I fill:#FFCC80,stroke:#333 style M fill:#4D8EDD,stroke:#333 style L fill:#FF4D4D,stroke:#333 style S fill:#FF4D4D,stroke:#333 style W fill:#AAAAAA,stroke:#333 style X fill:#AAAAAA,stroke:#333 style Q fill:#FFCC80,stroke:#333 style R fill:#FFCC80,stroke:#333 style K fill:#FF4D4D,stroke:#333 style N fill:#FFCC80,stroke:#333 ``` Chen Y, Palczewski K. (2016). Systems Pharmacology Links GPCRs with Retinal Degenerative Disorders. Annu Rev Pharmacol Toxicol;56:273-98.Rang & Dale's Pharmacology, Ninth Edition Rang & Dale's Pharmacology, Tenth Edition <table> <thead> <tr> <td><p>G$\alpha$ subunits$^{b}$</p></td> <td></td> <td></td> </tr> </thead> <tbody> <tr> <td><p>G$\alpha$ $_{\text{s}}$</p></td> <td><p>Stimulates adenylyl cyclase, causing increased cAMP formation</p></td> <td><p>Activated by cholera toxin, which blocks GTPase activity, thus preventing inactivation</p></td> </tr> <tr> <td><p>G$\alpha$ $_{\text{i}}$</p></td> <td><p>Inhibits adenylyl cyclase, decreasing cAMP formation</p></td> <td><p>Blocked by pertussis toxin, which prevents dissociation of $\alpha$$\beta$$\gamma$ complex</p></td> </tr> <tr> <td><p>G$\alpha$ $_{\text{o}}$</p></td> <td><p>Limited effects of $\alpha$ subunit (effects mainly due to $\beta$$\gamma$ subunits)</p></td> <td><p>Blocked by pertussis toxin. Occurs mainly in nervous system</p></td> </tr> <tr> <td><p>G$\alpha$ $_{\text{q}}$</p></td> <td><p>Activates phospholipase C, increasing production of second messengers inositol trisphosphate and diacylglycerol thus releasing Ca $^{2+}$ from intracellular stores and activating protein kinase C (PKC)</p></td> <td></td> </tr> <tr> <td><p>G$\alpha$ $_{12/13}$</p></td> <td><p>Activates Rho and thus Rho kinase</p></td> <td></td> </tr> <tr> <td><p>G$\beta$$\gamma$ subunits</p></td> <td><p>Activate potassium channels Inhibit voltage-gated calcium channels Activate GPCR kinases (GRKs) Activate mitogen-activated protein kinase cascade Interact with some forms of adenylyl cyclase and with phospholipase C$\beta$</p></td> <td><p>Many $\beta$$\gamma$ isoforms identified, but specific functions are not yet known</p></td> </tr> </tbody> </table> Rang & Dale's Pharmacology, Tenth Edition <table> <thead> <tr> <th colspan="3">Gα subunits<sup>b</sup></th> </tr> </thead> <tbody> <tr> <td>Gα <sub>s</sub></td> <td>Stimulates adenylyl cyclase, causing increased cAMP formation</td> <td>Activated by cholera toxin, which blocks GTPase activity, thus preventing inactivation</td> </tr> <tr> <td>Gα <sub>i</sub></td> <td>Inhibits adenylyl cyclase, decreasing cAMP formation</td> <td>Blocked by pertussis toxin, which prevents dissociation of αβγ complex</td> </tr> <tr> <td>Gα <sub>o</sub></td> <td>Limited effects of α subunit (effects mainly due to βγ subunits)</td> <td>Blocked by pertussis toxin. Occurs mainly in nervous system</td> </tr> <tr> <td>Gα <sub>q</sub></td> <td>Activates phospholipase C, increasing production of second messengers inositol trisphosphate and diacylglycerol thus releasing Ca <sup>2+</sup> from intracellular stores and activating protein kinase C (PKC)</td> <td></td> </tr> <tr> <td>Gα <sub>12/13</sub></td> <td>Activates Rho and thus Rho kinase</td> <td></td> </tr> <tr> <td>Gβγ subunits</td> <td> <ul> <li>Activate potassium channels</li> <li>Inhibit voltage-gated calcium channels</li> <li>Activate GPCR kinases (GRKs)</li> <li>Activate mitogen-activated protein kinase cascade</li> <li>Interact with some forms of adenylyl cyclase and with phospholipase Cβ</li> </ul> </td> <td>Many βγ isoforms identified, but specific functions are not yet known</td> </tr> </tbody> </table> Slide with "Review!" text **Type 3: Kinase linked receptors** Large heterogenous group responding mainly to protein mediators **Time scale:** hours **Location:** membrane **Effector:** protein kinases **Coupling:** direct **Structure:** single transmembrane helix- linking extracellular receptor domain to intracellular kinase domain **Receptor types** - Receptor tyrosine kinase – growth factors, insulin and IGF (insulin-like growth factor) - Receptor serine/threonine kinase – transforming growth factor - Cytokine receptor – interleukins and interferons - Receptor guanylate cyclase – natriuretic peptides <img src="kinasereceptor.png" alt="Diagram illustrating the structure of a kinase-linked receptor in the cell membrane. It shows the extracellular ligand-binding domain, the transmembrane $\alpha$ helix, and the intracellular kinase domain."> **Examples** Insulin Growth Factors Cytokine ANF receptors # **Type 3: Kinase linked receptors** Large heterogenous group responding mainly to protein mediators - **Time scale:** hours - **Location:** membrane - **Effector:** protein kinases - **Coupling:** direct - **Structure:** single transmembrane helix- linking extracellular receptor domain to intracellular kinase domain ## **Receptor types** - Receptor tyrosine kinase – growth factors, insulin and IGF (insulin-like growth factor) - Receptor serine/threonine kinase – transforming growth factor - Cytokine receptor – interleukins and interferons - Receptor guanylate cyclase – natriuretic peptides ## **Examples** - Insulin - Growth Factors - Cytokine - ANF receptors **Receptor tyrosine kinase** **Ras/Raf/MAP kinase pathway** 1. Ligand binding 2. Receptor dimerises 3. Tyrosine autophosphorylation 4. Binding of SH2- domain protein (Grb2) 5. Kinase cascade (Raf, Mek, MAPkinase) 6. Transcription factor 7. Gene transcription *Grb2- Growth factor receptor bound protein 2 (an adaptor protein); SH – Src homology Rang & Dale’s Pharmacology, Tenth Edition ```mermaid graph TD A[Growth factor] --> B{Receptor domain}; B --> C[Conformation change / Dimerisation]; C --> D[Tyrosine autophosphorylation]; D --> E[Phosphorylation of Grb2 / Binding of SH2-domain protein (Grb2)]; E --> F[Ras-GDP/GTP exchange Activation of Ras]; F --> G[Raf]; G --> H[Mek Phosphorylation]; H --> I[MAP kinase Phosphorylation]; I --> J[Various transcription factors Phosphorylation]; J --> K[Gene transcription NUCLEUS]; %% Other labels from the diagram subgraph Receptor B_receptor(Receptor domain); C_dimer(Dimerised receptor); D_phosph(Autophosphorylated receptor); E_grb2(Grb2 bound); B_receptor---Trans(Transmembrane $\alpha$ helix); B_receptor---TyrKinase(Tyrosine kinase domain); TyrKinase---TyrRes(Tyrosine residue); end subgraph KINASE CASCADE G; H; I; end ``` ## **Receptor tyrosine kinase** ### **Ras/Raf/MAP kinase pathway** 1. Ligand binding 2. Receptor dimerises 3. Tyrosine autophosphorylation 4. Binding of SH2- domain protein (Grb2) 5. Kinase cascade (Raf, Mek, MAPkinase) 6. Transcription factor 7. Gene transcription *Grb2- Growth factor receptor bound protein 2 (an adaptor protein); SH – Src homology Rang & Dale’s Pharmacology, Tenth Edition ```mermaid graph TD A[Growth factor] --> B{Receptor domain}; B --> C[Conformation change / Dimerisation]; C --> D[Tyrosine autophosphorylation]; D --> E[Phosphorylation of Grb2 / Binding of SH2-domain protein (Grb2)]; E --> F[Ras-GDP/GTP exchange Activation of Ras]; F --> G[Raf]; G --> H[Mek Phosphorylation]; H --> I[MAP kinase Phosphorylation]; I --> J[Various transcription factors Phosphorylation]; J --> K[Gene transcription NUCLEUS]; %% Other labels from the diagram subgraph Receptor B_receptor(Receptor domain); C_dimer(Dimerised receptor); D_phosph(Autophosphorylated receptor); E_grb2(Grb2 bound); B_receptor---Trans(Transmembrane $\alpha$ helix); B_receptor---TyrKinase(Tyrosine kinase domain); TyrKinase---TyrRes(Tyrosine residue); end subgraph KINASE CASCADE G; H; I; end ``` **Receptor tyrosine kinase** **Jak/stat pathway** ```mermaid graph TD A[Cytokine] --> B{Receptor} B -- Ligand binding --> C{Dimerisation<br>Conformation change<br>activation of Jak} C --> D{Phosphorylation of receptor<br>+ Jak} D -- Binding and phosphorylation of SH2-domain (Stat) --> E[Stat<br>SH2-domain protein] E --> F{Dimerisation of Stat} F --> G[Gene transcription<br>in NUCLEUS] D -- Location --> MEMBRANE subgraph Steps 1(Ligand binding) 2(Receptor dimerises) 3(Phosphorylation of receptor and Jak) 4(Binding of SH2- domain protein (Stat)) 5(Dimerization of Stat) 6(Gene transcription) end ``` *JAK – Janus kinase; STAT – signal transducer and activator of activator of transcription Rang & Dale’s Pharmacology, Tenth Edition ## **Receptor tyrosine kinase** ### **Jak/stat pathway** ```mermaid graph TD A[Cytokine] --> B{Receptor} B -- Ligand binding --> C{Dimerisation<br>Conformation change<br>activation of Jak} C --> D{Phosphorylation of receptor<br>+ Jak} D -- Binding and phosphorylation of SH2-domain (Stat) --> E[Stat<br>SH2-domain protein] E --> F{Dimerisation of Stat} F --> G[Gene transcription<br>in NUCLEUS] D -- Location --> MEMBRANE subgraph Steps 1(Ligand binding) 2(Receptor dimerises) 3(Phosphorylation of receptor and Jak) 4(Binding of SH2- domain protein (Stat)) 5(Dimerization of Stat) 6(Gene transcription) end ``` *JAK – Janus kinase; STAT – signal transducer and activator of activator of transcription Rang & Dale’s Pharmacology, Tenth Edition Slide with the word "Review!" centered on a blue gradient background **Type 4: Nuclear receptors** Regulate gene transcription, metabolic and developmental processes Not always in the nucleus **Time scale**: Hours **Location**: intracellular **Effector**: Gene transcription **Coupling**: via DNA **Structure**: monomeric proteins typically composed of several domains each with distinct functions * N-terminal domain * Core domain * Hinge Region * C-terminal domain <img src='nuclear_receptor_domains.png' alt='Diagram showing the domains of a nuclear receptor: N-terminal Domain (includes AF-1), DNA Binding Domain (DBD), Hinge, Ligand Binding Domain (LBD) (includes AF-2), and C-terminal Domain.'> **Examples** **Steroid hormones** **Thyroid hormones** **Retinoic acid** **Vitamin D receptors** | Class I: Steroid Receptors (SR) | Class II: Retinoid X Receptor (RXR) Heterodimers | | :---: | :---: | | <img src='class_i_receptor.png' alt='SR receptors dimerized on DNA'> | <img src='class_ii_receptor.png' alt='RXR and R receptors heterodimerized on DNA'> | | Glucocorticoid Mineralocorticoid Progesterone Estrogen | Thyroid hormone RAR $\alpha$|$\beta$|$\gamma$ | | Class III: Dimeric Orphan Receptors (DOR) | Class IV: Monomeric Orphan Receptors (MOR) | | <img src='class_iii_receptor.png' alt='DOR receptors dimerized on DNA'> | <img src='class_iv_receptor.png' alt='MOR receptor monomer on DNA'> | # **Type 4: Nuclear receptors** Regulate gene transcription, metabolic and developmental processes Not always in the nucleus - **Time scale**: Hours - **Location**: intracellular - **Effector**: Gene transcription - **Coupling**: via DNA - **Structure**: monomeric proteins typically composed of several domains each with distinct functions - N-terminal domain - Core domain - Hinge Region - C-terminal domain ## **Examples** - **Steroid hormones** - **Thyroid hormones** - **Retinoic acid** - **Vitamin D receptors** | Class I: Steroid Receptors (SR) | Class II: Retinoid X Receptor (RXR) Heterodimers | | :---: | :---: | | | | | Glucocorticoid Mineralocorticoid Progesterone Estrogen | Thyroid hormone RAR $\alpha$|$\beta$|$\gamma$ | | Class III: Dimeric Orphan Receptors (DOR) | Class IV: Monomeric Orphan Receptors (MOR) | | | | **Type 4: Nuclear receptors** **Steroid Receptors (Class I)** * Steroid hormones are lipophilic and can easily enter cell membranes * Lipophilic ligands interact with nuclear receptors once inside the cell * Functional effects of nuclear receptors are slow due to their role in gene transcription and protein synthesis * In the absence of ligand, nuclear receptors are mostly in the cytoplasm, bound to heat shock proteins (HSPs) mermaid graph TD A[Outside of cell] -->|Steroid hormone| B(Cell membrane) B --> C[Inside of cell] C --> D(Steroid hormone) --Entrance--> E{Steroid receptor} D --> F(Hormone-receptor complex) G[Inside of cell] --> F F --> H[Nucleus] H --> I[Complex binds to sites on DNA] I --> J[Cellular response] subgraph Diagram: Steroid Receptors (Class I) direction LR A B C H end style D fill:#FFA07A,stroke:#333 style E fill:#FFA07A,stroke:#333 style F fill:#F08080,stroke:#333 style G fill:#F08080,stroke:#333 style H fill:#E0BBE4,stroke:#333 style I fill:#E0BBE4,stroke:#333 style J fill:#E9E1FF,stroke:#333 style B fill:#C0F4C0,stroke:#333 style C fill:#E9E1FF,stroke:#333 style H fill:#E0BBE4,stroke:#333 style H fill:#E0BBE4,stroke:#333 style H fill:#E0BBE4,stroke:#333 style H fill:#E0BBE4,stroke:#333 style E fill:#FFA07A,stroke:#333 style F fill:#FFA07A,stroke:#333 style I fill:#FFA07A,stroke:#333 style J fill:#FFB6C1,stroke:#333 style A fill:#E9E1FF,stroke:#333 style G fill:#E9E1FF,stroke:#333 style D fill:#FFA07A,stroke:#333 style E fill:#FFB6C1,stroke:#333 style F fill:#FFA07A,stroke:#333 style I fill:#FFB6C1,stroke:#333 style J fill:#FBEFFF,stroke:#333 style H fill:#F08080,stroke:#333 style G fill:#FFB6C1,stroke:#333 subgraph Cell direction TB Outside_of_cell Cell_membrane Inside_of_cell end Steroid_hormone(Steroid hormone) Steroid_hormone --> Inside_of_cell Inside_of_cell --> Steroid_receptor_inactive(Steroid receptor) Steroid_hormone --> Hormone_receptor_complex_active(Hormone-receptor complex) Steroid_receptor_inactive --- Hormone_receptor_complex_active Hormone_receptor_complex_active --> Nucleus_membrane[Inside Nucleus] Nucleus_membrane --> Complex_binds_to_sites_on_DNA(Complex binds to sites on DNA) Complex_binds_to_sites_on_DNA --> Cellular_response(Cellular response) # **Type 4: Nuclear receptors** ## **Steroid Receptors (Class I)** - Steroid hormones are lipophilic and can easily enter cell membranes - Lipophilic ligands interact with nuclear receptors once inside the cell - Functional effects of nuclear receptors are slow due to their role in gene transcription and protein synthesis - In the absence of ligand, nuclear receptors are mostly in the cytoplasm, bound to heat shock proteins (HSPs) ```mermaid graph TD subgraph Cell direction TB Outside_of_cell Cell_membrane Inside_of_cell end Steroid_hormone(Steroid hormone) Steroid_hormone --> Inside_of_cell Inside_of_cell --> Steroid_receptor_inactive(Steroid receptor) Steroid_hormone --> Hormone_receptor_complex_active(Hormone-receptor complex) Steroid_receptor_inactive --- Hormone_receptor_complex_active Hormone_receptor_complex_active --> Nucleus_membrane[Inside Nucleus] Nucleus_membrane --> Complex_binds_to_sites_on_DNA(Complex binds to sites on DNA) Complex_binds_to_sites_on_DNA --> Cellular_response(Cellular response) ``` **Type 4: Nuclear receptors** **Steroid Receptors (Class II)** * Operate as heterodimers with RXR * **Two types of heterodimers:** * Non-permissive: activated only by RXR ligand * Permissive: activated by retinoic acid or partner ligand * Typically bound to co-repressor proteins to suppress gene expression * Ligand binding causes dissociation of co-repressors and recruitment of co-activators * Co-activator recruitment initiates gene expression ```mermaid graph TD A[Hormone] --> B(Nuclear pore); B --> C{Receptor Heterodimer with Corepressor (LBD: Ligand Binding Domain, DBD: DNA Binding Domain, RXR: Retinoid X Receptor, T/R: Thyroid/Retinoic Acid Receptor) bound to HRE on target gene}; style C fill:#faa, stroke:#ff0000, color:#000000; A --> C; C --> D[Dissociation of Corepressor and Recruitment of Coactivator and RNA Polymerase]; style D fill:#ddf, stroke:#00aa00, color:#000000; D --> E[Transcription of target gene: mRNA]; D --> F[RNA Polymerase]; E --> G(Nuclear pore); G --> H[Ribosome in Cytoplasm]; H --> I[Protein synthesis]; I --> J[Changed cell function]; subgraph Cytoplasm K[Cytoplasm]; L[Nuclear envelope]; end subgraph Nucleus M[Nucleus]; C; D; E; F; end ``` # **Type 4: Nuclear receptors** ## **Steroid Receptors (Class II)** - Operate as heterodimers with RXR - **Two types of heterodimers:** - Non-permissive: activated only by RXR ligand - Permissive: activated by retinoic acid or partner ligand - Typically bound to co-repressor proteins to suppress gene expression - Ligand binding causes dissociation of co-repressors and recruitment of co-activators - Co-activator recruitment initiates gene expression ```mermaid graph TD subgraph Nucleus M[Nucleus]; C; D; E; F; end subgraph Cytoplasm K[Cytoplasm]; L[Nuclear envelope]; end A[Hormone] --> B(Nuclear pore); B --> C{Receptor Heterodimer with Corepressor (LBD: Ligand Binding Domain, DBD: DNA Binding Domain, RXR: Retinoid X Receptor, T/R: Thyroid/Retinoic Acid Receptor) bound to HRE on target gene}; style C fill:#faa, stroke:#ff0000, color:#000000; A --> C; C --> D[Dissociation of Corepressor and Recruitment of Coactivator and RNA Polymerase]; style D fill:#ddf, stroke:#00aa00, color:#000000; D --> E[Transcription of target gene: mRNA]; D --> F[RNA Polymerase]; E --> G(Nuclear pore); G --> H[Ribosome in Cytoplasm]; H --> I[Protein synthesis]; I --> J[Changed cell function]; ``` Slide with the single word "Review!" centered on a gradient blue background **Key information** * Most drugs bind to, and act through receptors * Majority of drugs receptors are proteins * Four superfamilies of receptors are presented * Effects of drug after binding to a receptor is called signal transduction * Agonists at a given at a given receptor can be distinguished based upon affinity and efficacy * Antagonists are drugs that bind to receptors and block the effects of agonists # **Key information** - Most drugs bind to, and act through receptors - Majority of drugs receptors are proteins - Four superfamilies of receptors are presented - Effects of drug after binding to a receptor is called signal transduction - Agonists at a given at a given receptor can be distinguished based upon affinity and efficacy - Antagonists are drugs that bind to receptors and block the effects of agonists **References** * Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, editors. *Rang & Dale’s pharmacology*. 10th ed. Edinburgh: Elsevier; 2023 * Becker DE, Reed KL. *Pharmacology and Therapeutics for Dentistry*. 7th ed. St. Louis: Elsevier; 2017. * Bullock S, Manias E. *Fundamentals of pharmacology*. 8th ed. Frenchs Forest, NSW: Pearson Australia; 2017 * Stringer JL. *Basic concepts in pharmacology*. 6th ed. New York (US): McGraw Hill Medical; 2022 Feb 18 Images of people suffering from illnesses and medication jars. # **References** - Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, editors. *Rang & Dale’s pharmacology*. 10th ed. Edinburgh: Elsevier; 2023 - Becker DE, Reed KL. *Pharmacology and Therapeutics for Dentistry*. 7th ed. St. Louis: Elsevier; 2017. - Bullock S, Manias E. *Fundamentals of pharmacology*. 8th ed. Frenchs Forest, NSW: Pearson Australia; 2017 - Stringer JL. *Basic concepts in pharmacology*. 6th ed. New York (US): McGraw Hill Medical; 2022 Feb 18 Images of people suffering from illnesses and medication jars. [[L2 PHARMACODYNAMICS 2025.pdf#page=1|L2 PHARMACODYNAMICS 2025, p.1]] [[L2 PHARMACODYNAMICS 2025.pdf#page=3|L2 PHARMACODYNAMICS 2025, p.3]] [[L2 PHARMACODYNAMICS 2025.pdf#page=4|L2 PHARMACODYNAMICS 2025, p.4]] [[L2 PHARMACODYNAMICS 2025.pdf#page=5|L2 PHARMACODYNAMICS 2025, p.5]] [[L2 PHARMACODYNAMICS 2025.pdf#page=7|L2 PHARMACODYNAMICS 2025, p.7]] [[L2 PHARMACODYNAMICS 2025.pdf#page=8|L2 PHARMACODYNAMICS 2025, p.8]] [[L2 PHARMACODYNAMICS 2025.pdf#page=9|L2 PHARMACODYNAMICS 2025, p.9]] [[L2 PHARMACODYNAMICS 2025.pdf#page=10|L2 PHARMACODYNAMICS 2025, p.10]] [[L2 PHARMACODYNAMICS 2025.pdf#page=11|L2 PHARMACODYNAMICS 2025, p.11]] [[L2 PHARMACODYNAMICS 2025.pdf#page=12|L2 PHARMACODYNAMICS 2025, p.12]] [[L2 PHARMACODYNAMICS 2025.pdf#page=13|L2 PHARMACODYNAMICS 2025, p.13]] [[L2 PHARMACODYNAMICS 2025.pdf#page=14|L2 PHARMACODYNAMICS 2025, p.14]] [[L2 PHARMACODYNAMICS 2025.pdf#page=15|L2 PHARMACODYNAMICS 2025, p.15]] [[L2 PHARMACODYNAMICS 2025.pdf#page=16|L2 PHARMACODYNAMICS 2025, p.16]] [[L2 PHARMACODYNAMICS 2025.pdf#page=17|L2 PHARMACODYNAMICS 2025, p.17]] [[L2 PHARMACODYNAMICS 2025.pdf#page=18|L2 PHARMACODYNAMICS 2025, p.18]] [[L2 PHARMACODYNAMICS 2025.pdf#page=19|L2 PHARMACODYNAMICS 2025, p.19]] [[L2 PHARMACODYNAMICS 2025.pdf#page=20|L2 PHARMACODYNAMICS 2025, p.20]] [[L2 PHARMACODYNAMICS 2025.pdf#page=21|L2 PHARMACODYNAMICS 2025, p.21]] [[L2 PHARMACODYNAMICS 2025.pdf#page=22|L2 PHARMACODYNAMICS 2025, p.22]] [[L2 PHARMACODYNAMICS 2025.pdf#page=23|L2 PHARMACODYNAMICS 2025, p.23]] [[L2 PHARMACODYNAMICS 2025.pdf#page=24|L2 PHARMACODYNAMICS 2025, p.24]] [[L2 PHARMACODYNAMICS 2025.pdf#page=25|L2 PHARMACODYNAMICS 2025, p.25]] [[L2 PHARMACODYNAMICS 2025.pdf#page=26|L2 PHARMACODYNAMICS 2025, p.26]] [[L2 PHARMACODYNAMICS 2025.pdf#page=27|L2 PHARMACODYNAMICS 2025, p.27]] [[L2 PHARMACODYNAMICS 2025.pdf#page=28|L2 PHARMACODYNAMICS 2025, p.28]] [[L2 PHARMACODYNAMICS 2025.pdf#page=29|L2 PHARMACODYNAMICS 2025, p.29]] [[L2 PHARMACODYNAMICS 2025.pdf#page=30|L2 PHARMACODYNAMICS 2025, p.30]] [[L2 PHARMACODYNAMICS 2025.pdf#page=31|L2 PHARMACODYNAMICS 2025, p.31]] [[L2 PHARMACODYNAMICS 2025.pdf#page=32|L2 PHARMACODYNAMICS 2025, p.32]] [[L2 PHARMACODYNAMICS 2025.pdf#page=33|L2 PHARMACODYNAMICS 2025, p.33]] [[L2 PHARMACODYNAMICS 2025.pdf#page=34|L2 PHARMACODYNAMICS 2025, p.34]] [[L2 PHARMACODYNAMICS 2025.pdf#page=35|L2 PHARMACODYNAMICS 2025, p.35]] [[L2 PHARMACODYNAMICS 2025.pdf#page=36|L2 PHARMACODYNAMICS 2025, p.36]] [[L2 PHARMACODYNAMICS 2025.pdf#page=37|L2 PHARMACODYNAMICS 2025, p.37]] [[L2 PHARMACODYNAMICS 2025.pdf#page=38|L2 PHARMACODYNAMICS 2025, p.38]] [[L2 PHARMACODYNAMICS 2025.pdf#page=39|L2 PHARMACODYNAMICS 2025, p.39]] [[L2 PHARMACODYNAMICS 2025.pdf#page=40|L2 PHARMACODYNAMICS 2025, p.40]]