Pharma - Berto - L2 part 2

Receptors Overview

• Receptors are primary drug targets, influencing cell physiology through interaction with drugs.
• They trigger transduction systems that lead to specific cellular responses.
• Most drugs interact with receptors for endogenous mediators.

Classification of Receptors

• Receptors are classified based on their localization:
  • Membrane receptors (majority):
    • Ionotropic receptors: Form channels and act quickly (milliseconds).
    • Tyrosine kinase (TK) receptors: Characterized by tyrosine kinase activity, slower action.
    • Metabotropic receptors: G-protein-coupled, activate secondary messengers, slower response (seconds).
  • Intracellular receptors: Respond to lipophilic signal molecules, slower action (hours), interact with DNA.

Neurotransmitter-Receptor Interaction

• Neurotransmitters (NTs) can elicit rapid or slow responses depending on the receptor type:
  • Acetylcholine:
    • Rapid response with nicotinic receptors (ionotropic).
    • Slower response with muscarinic receptors (metabotropic).
• Other examples include GABA, glutamate, serotonin, and ATP with distinct receptor interactions.

Ionotropic vs Metabotropic Receptors

• Ionotropic receptors:
  • Comprise multiple subunits (4 or 5).
  • Act without second messengers, lead to rapid ion flux.
• Metabotropic receptors:
  • Consist of a single subunit with 7 transmembrane domains.
  • Activate second messengers for slower but prolonged actions.

G-Protein Coupled Receptors

• Metabotropic receptors activate G-proteins with three subunits: α, β, and γ.
• G-proteins have GTPase activity, hydrolyzing GTP to GDP, which activates effectors and second messengers.
• Major G-protein families:
  • Gs: Stimulates adenylyl cyclase (AC).
  • Gi/Go: Inhibits AC.
  • Gt: Important in vision.
  • Gq: Activates phospholipase C (PLC).

G-Protein Activation Cycle

• Unbound receptors do not interact with G-proteins.
• Ligand binding causes a conformational change, activating G-proteins.
• Activated α subunit interacts with effectors, while β and γ maintain receptor interaction and modulate activity.

Toxins and G-Protein Interaction

• Cholera toxin: Constitutively activates Gs, leading to continuous AC activation.
• Pertussis toxin: Inhibits Gi, blocking transduction.

G-Protein Effectors

• Effectors are enzymes (e.g., AC, PLC) or ion channels that facilitate cellular responses.
• Second messengers (e.g., cAMP, Ca²⁺) mediate intracellular signaling cascades.

Ion Channels

• Ion channels can be voltage-gated or ligand-gated (e.g., ionotropic receptors).
• Ionotropic channels:
  • Feature rapid kinetics and provide selective ion conductance.
  • Can lead to hyperpolarization or depolarization.

GABA A and Glycine Receptors

• GABA A receptors: Main inhibitory ionotropic receptors, modulated by various drugs (e.g., benzodiazepines).
• Glycine receptors: Similar to GABA A but with more limited distribution.

Ionotropic Glutamate Receptors

• Types include AMPA and NMDA receptors, essential for excitatory neurotransmission.
• AMPA receptors: Mediates fast transmission and can be modulated by RNA editing and alternative splicing.
• NMDA receptors: Require both ligand binding and depolarization for activation due to magnesium blockade.

Receptor-Tyrosine Kinases (RTKs)

• RTKs are key for cell signaling related to growth and differentiation.
• Ligands include hormones and growth factors; dysfunctional RTK can lead to cancer.

Intracellular Receptors

• Intracellular receptors, like those for sex hormones and glucocorticoids, act by diffusing across the membrane.
• They may interact directly with DNA or carry out non-genomic actions, influencing multiple cellular pathways.

Summary

• Understanding receptor types and their mechanisms is crucial in pharmacology and therapeutic development.
• Targeting specific receptor pathways can provide insights into treating various diseases and conditions.### Estrogen Receptors and SERM
• Selective Estrogen Receptor Modulators (SERM) can act as either agonists or antagonists.
• The tissue type, binding site, and brain area determine the action of SERMs.
• Estrogen receptors are classified into two types: α (alpha) and β (beta).

Ligand Interactions

• Estrogen receptors have a broad binding site that allows interaction with various ligands.
• Genistein, a natural ligand derived from soy, acts as an endocrine disruptor by mimicking sexual hormones.
• Endocrine disruptors interfere with the normal development of organisms.

Receptor Interactions

• Different receptors, like G-protein coupled receptors and tyrosine kinase receptors, can interact through shared intracellular pathways.
• Types of interactions include:
  • Convergence
  • Divergence
  • Amplification (cross-talk)
  • Regulation (through cross-talk)

Drug Targets and Molecular Regulation

• Drug targets extend beyond standard receptors to include those regulating molecular transport and membrane electrical activity.
• Membrane transport systems, such as pumps and carriers, are crucial for pharmacological effects.
• Selective Serotonin Reuptake Inhibitors (SSRIs) inhibit monoamine transport, highlighting their importance in pharmacology.

Explore the role of receptors in drug action and their classification. This quiz covers how drugs change cell physiology and interact with receptors on cell membranes or intracellularly. Test your knowledge on the different types of receptors and their functions.