Receptors are crucial for drug action, serving as cellular targets that initiate various signaling mechanisms. From G protein-coupled receptors to ion channels, each type plays a unique role in transmitting signals across cell membranes and within cells.

Understanding receptor types and signaling mechanisms is essential for grasping how drugs work in the body. This knowledge forms the foundation for pharmacodynamics, helping us comprehend drug-receptor interactions and their effects on cellular function and physiological responses.

Receptor Types for Drug Action

G Protein-Coupled Receptors and Ion Channels

• G protein-coupled receptors (GPCRs) form the largest family of membrane receptors
  • Characterized by seven transmembrane domains
  • Associate with G proteins for signal transduction
  • Examples include β-adrenergic receptors (regulate heart rate) and dopamine receptors (involved in mood regulation)
• Ion channels create pores in cell membranes for specific ion passage
  • Respond to various stimuli (ligand binding, membrane potential changes)
  • Regulate ion concentrations and membrane potential
  • Examples include voltage-gated sodium channels (crucial for action potential generation) and ligand-gated GABA receptors (mediate inhibitory neurotransmission)

Nuclear Receptors and Enzyme-Linked Receptors

• Nuclear receptors function as intracellular proteins activated by lipophilic ligands
  • Directly regulate gene expression by binding to specific DNA sequences
  • Examples include steroid hormone receptors (estrogen receptor, glucocorticoid receptor) and thyroid hormone receptors
• Enzyme-linked receptors possess intrinsic enzymatic activity or associate directly with enzymes
  • Initiate signaling cascades upon ligand binding
  • Examples include receptor tyrosine kinases (insulin receptor, epidermal growth factor receptor)

Integrins and Their Unique Properties

• Integrins act as transmembrane receptors mediating cell-cell and cell-extracellular matrix interactions
  • Play crucial roles in cell adhesion and signal transduction
  • Exhibit bidirectional signaling capabilities
  • Examples include αIIbβ3 integrin (platelet aggregation) and α4β1 integrin (leukocyte adhesion)

Signaling Mechanisms of Receptors

G Protein-Coupled Receptor Signaling

• GPCRs activate heterotrimeric G proteins upon ligand binding
  • Lead to modulation of various effector proteins and second messenger systems
  • G protein subtypes (Gs, Gi, Gq) determine specific downstream effects
  • Example: β2-adrenergic receptor activation leads to increased cAMP production via Gs protein
• GPCR signaling involves multiple steps
  • Ligand binding causes conformational change in receptor
  • G protein activation and dissociation of α and βγ subunits
  • Modulation of effector proteins (adenylyl cyclase, phospholipase C)

Ion Channel and Nuclear Receptor Signaling

• Ion channels alter membrane potential and ion concentrations
  • Allow selective passage of ions across cell membrane
  • Respond to specific stimuli (voltage changes, ligand binding)
  • Example: Acetylcholine binding to nicotinic receptors causes sodium influx and depolarization
• Nuclear receptors undergo conformational changes upon ligand binding
  • Dimerize and bind to specific DNA sequences
  • Recruit co-activators or co-repressors to regulate gene transcription
  • Example: Estrogen binding to estrogen receptor leads to increased transcription of genes involved in cell proliferation

Enzyme-Linked Receptor and Integrin Signaling

• Enzyme-linked receptors autophosphorylate upon ligand binding
  • Create docking sites for signaling proteins
  • Initiate intracellular signaling cascades
  • Example: Insulin binding to insulin receptor triggers tyrosine kinase activity and glucose uptake
• Integrins transmit signals bidirectionally
  • "Outside-in" signaling triggered by extracellular ligand binding
  • "Inside-out" signaling modulates integrin affinity and avidity from within the cell
  • Example: Fibronectin binding to α5β1 integrin initiates focal adhesion formation and cell spreading

Second Messengers in Signal Transduction

Cyclic Nucleotides and Lipid-Derived Second Messengers

• Cyclic AMP (cAMP) acts as a key second messenger
  • Produced by adenylyl cyclase in response to G protein activation
  • Regulates various cellular processes through protein kinase A activation
  • Example: cAMP elevation in cardiac myocytes increases heart rate and contractility
• Inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) function as second messengers
  • Generated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C
  • IP3 releases calcium from intracellular stores
  • DAG activates protein kinase C
  • Example: Angiotensin II receptor activation leads to IP3 and DAG production, causing vasoconstriction

Ionic and Gaseous Second Messengers

• Calcium ions (Ca2+) serve as versatile second messengers
  • Intracellular concentration tightly regulated by pumps, channels, and binding proteins
  • Trigger various cellular responses (neurotransmitter release, muscle contraction)
  • Example: Calcium influx in presynaptic neurons triggers synaptic vesicle fusion and neurotransmitter release
• Nitric oxide (NO) acts as a gaseous second messenger
  • Diffuses across cell membranes
  • Activates guanylyl cyclase to produce cyclic GMP (cGMP)
  • Example: NO production in endothelial cells causes smooth muscle relaxation and vasodilation

Integration of Second Messenger Systems

• Second messengers often work in concert
  • Create complex signaling networks
  • Allow for fine-tuned regulation of cellular responses to external stimuli
  • Example: Calcium and DAG synergistically activate protein kinase C in many cell types
• Cross-talk between second messenger systems occurs
  • Enables integration of multiple signaling pathways
  • Provides mechanisms for signal amplification or attenuation
  • Example: cAMP-dependent protein kinase A can modulate calcium signaling by phosphorylating calcium channels

Receptor Regulation: Desensitization vs Sensitization

Mechanisms of Receptor Desensitization

• Desensitization decreases receptor responsiveness following continuous or repeated stimulation
  • Protects cells from overstimulation
  • Involves multiple molecular mechanisms
• Homologous desensitization targets specific activated receptors
  • Downregulates receptors activated by a particular ligand
  • Example: Prolonged exposure to β-agonists leads to β-adrenergic receptor desensitization in airway smooth muscle
• Heterologous desensitization affects unrelated receptor types
  • Activation of one receptor type leads to desensitization of others
  • Example: Activation of protein kinase C by one GPCR can desensitize other GPCRs in the same cell

Receptor Sensitization and Long-Term Regulation

• Sensitization increases receptor responsiveness
  • Often occurs in response to low-level or intermittent stimulation
  • Enhances cellular responses to subsequent stimuli
  • Example: Repeated low-dose cocaine administration increases dopamine receptor sensitivity
• Long-term receptor regulation involves changes in gene expression
  • Alters receptor protein synthesis and degradation
  • Allows cells to adapt to chronic changes in signaling environment
  • Example: Chronic opioid use leads to increased expression of adenylyl cyclase, contributing to tolerance

Molecular Mechanisms of Receptor Regulation

• Receptor internalization (endocytosis) regulates surface availability
  • Influences cellular responsiveness to ligands
  • Can lead to receptor degradation or recycling
  • Example: β2-adrenergic receptors undergo rapid internalization upon agonist binding
• Receptor phosphorylation by kinases plays a key role in desensitization
  • G protein-coupled receptor kinases (GRKs) phosphorylate activated GPCRs
  • β-arrestin recruitment follows phosphorylation, leading to receptor uncoupling
  • Example: GRK-mediated phosphorylation of μ-opioid receptors contributes to morphine tolerance