Drug-Receptor Binding and Signal Transduction

Drug-Receptor Binding & Signal Transduction

• A drug is any chemical that interacts with a protein or other molecule to cause a cellular response. Drugs can be endogenous (made in the body) or exogenous (delivered to the body). Examples of exogenous drugs include poisons and toxins.
• A receptor is a protein that interacts with a molecule and triggers changes in downstream signaling pathways.

Drug-Receptor Binding

• Drugs bind to receptors via chemical bonds. Types of bonds include covalent (strong), hydrogen, electrostatic, and van der Waals forces (weak).
• Agonists are drugs that bind to a receptor and activate it.
• Antagonists are drugs that bind to a receptor and inactivate it.
• Different receptors have different binding sites and mechanisms of action.

Parts of an Atom

• Protons are subatomic particles with a positive electrical charge.
• Electrons are subatomic particles with a negative electrical charge.
• Neutrons are subatomic particles with no electrical charge.

Blood-Brain Barrier (BBB)

• The BBB protects the brain from many substances in general circulation.
• The BBB is formed by tight junctions between endothelial cells that make up the blood vessels of the central nervous system.
• The vessel of the central nervous system is surrounded by cells called pericytes and astrocytes that form a basement membrane and a protective layer to keep drugs out of the brain tissue.
• Lipophilic drugs can diffuse through the membranes while non-lipophilic drugs cannot, unless they have a transporter.
• Other tricks to get the drug across the BBB include binding the drug to a transporter or giving a stimulus to transiently open the BBB.

Signal Transduction Mechanisms

• Signal transduction mechanisms are processes in which one type of signal converts into another signal
• There are various signal transduction mechanisms including
  • Ion channels
  • G protein-coupled receptors (GPCRs)
  • Enzyme-linked receptors
  • Nuclear receptors

G-protein coupled receptors (GPCRs)

• GPCRs are a complex of alpha, beta, and gamma subunits that bind GTP/GDP.
• GPCRs can bind to various ligands, such as odorants, pheromones, and endogenous molecules.

GPCR Signaling Pathways

• Cholera toxin persists activation of G proteins by blocking GTPase activity.
• Pertussis toxin prevents G proteins from coupling receptors.

Second messengers

• Calcium- influx through channels or release from intracellular stores (endoplasmic reticulum). 2nd messengers include, cyclic nucleotides- cAMP or cGMP from adenylyl or guanylyl cyclase, respectively, and phospholipase C that breaks down phosphatidylinositol into IP3 and DAG. Arachidonic acid (AA), metabolized by cyclooxygenase (COX) or lipoxygenase enzymes into numerous bioactive substances.

Effectors downstream of Ca++

• Calmodulin binds to Ca++ via 4 EF-hand domains, activating CaMK, calcineurin (a phosphatase), MAPK, and phosphodiesterase (PDE). CaMK is also regulated through a catalytic and regulatory domain.
• Protein Kinase C- phosphorylates many proteins.
• MEK which is a mitogen activated protein kinase (MAPK)/extracellular signal-related kinase (ERK).
• Phosphoinositide kinase 3 (PI3K) which phosphorylates protein kinase B (also known as Akt).

Cyclic Nucleotides

• Cyclic AMP (cAMP) is produced by adenylyl cyclase (AC)
• GPCRs coupled to G, stimulate AC while those coupled to G, inhibit AC.
• cAMP is a ligand for ion channels. Activates Protein Kinase A (PKA) that phosphorylates cyclic AMP response element-binding protein (CREB)
• Cyclic GMP (cGMP) produced by guanylyl cyclase (GC).
• cGMP regulates ion channels, relaxes smooth muscle. Activates Protein Kinase G (PKG)
• Nitrates are used as vasodilators that activate GC, increase cGMP and dilate vessels.

Phospholipase C (PLC)

• PLC catalyzes the breakdown of phosphatidylinositol in two second messenger products including IP₃ and DAG
• PLC is commonly activated by G_q proteins, specifically the βγ subunits.
• IP₃ binds to the IP₃ receptor on the ER and opens a Ca⁺⁺ channel.
• Ca⁺⁺ is pumped into the ER, and DAG (along with Ca⁺⁺) activates protein kinase C (PKC).

Arachidonic acid (AA) metabolites

• AA is an eicosanoid with 20 carbons that can be cleaved out from the membrane by phospholipase A2. Activated by Ca++ and phosphorylation mediated by MAPKs.
• AA metabolites include leukotrienes from 5-lipoxygenase (5-LO), and prostaglandins and prostacyclin from cyclooxygenase (COX).
• COX1 and COX2 convert AA to prostaglandins and other important molecules for the gastrointestinal tract and inflammation.

Enzyme-linked Receptors

• Cytokine receptors, tyrosine kinase receptors, and serine/threonine kinase receptors.
• Ligands for enzyme-linked receptors include cytokines, growth factors, and hormones.

Tyrosine Kinase Receptors

• Dimerization and autophosphorylation are critical for signaling in tyrosine kinase receptors. This involves multiple steps such as receptors being activated by growth factors and phosphorylating tyrosine residue, and triggering a cascade of phosphorylation events that lead to various cellular responses.

Nuclear Receptors

• Ligands for Nuclear receptors must be able to cross the plasma membrane to bind to the intracellular receptor.

This lesson delves into drug-receptor interactions and signal transduction pathways. It covers drug and receptor definitions, binding mechanisms such as covalent and non-covalent bonds, and the roles of agonists versus antagonists. Learn about the different receptor binding sites.