Signaling Molecules & Receptors Overview

Signaling Molecule Landscape

• Core chemical messengers discussed in physiology:
  • Hormones (endocrine origin; released from epithelial-derived glandular tissue, travel via blood)
  • Neurotransmitters (neuronal origin; released from axon terminals into synaptic clefts)
• Other categories exist (paracrines, autocrines, “factors”), but lecture focuses on hormones & neurotransmitters.

Receptors – Fundamental Attributes

• Protein nature: Almost all receptors are integral membrane proteins that span the plasma membrane.
• Necessity: Without a receptor, a signaling molecule elicits no intracellular response.
• Specificity:
  • Receptor–ligand interaction obeys “lock-and-key” rules of shape & biochemical affinity.
  • One receptor may accept a single ligand or a small ligand family.
• Location dictated by ligand polarity:
  • Polar / lipophobic ligands (e.g., ACh, NE, insulin) cannot cross lipid bilayer → receptors positioned on extracellular surface.
  • Non-polar / lipophilic ligands (e.g., steroid hormones) diffuse across membrane → receptors reside in cytoplasm or nucleus.
• Conformational change: Ligand binding ➜ protein shape shift ➜ initiates downstream events (gate opening, G-protein activation, enzyme catalysis, etc.).

Ligand-Gated Ion Channels (LGICs)

• Dual function: receptor + ion channel.
• Mechanism sequence:
  1. Ligand binds external docking site.
  2. Conformational change flips “gate” from closed to open.
  3. Ion(s) diffuse down electrochemical gradient; typical example = Na^+ influx.
  4. Resulting depolarization is often only an intermediate step (→ neurotransmitter or insulin release, action potential initiation, etc.).
• Membrane potential context: interior initially negative; Na^+ entry diminishes negativity (= depolarization).
• Canonical example: Cholinergic nicotinic receptor
  • Ligand: Acetylcholine (ACh)
  • Ion: commonly Na^+ (may allow K^+, Ca^{2+} in subtypes)
  • Distribution: neuromuscular junction, autonomic ganglia, CNS.

G-Protein–Coupled / Linked Receptors (GPCRs)

• Architecture:
  • Receptor (7-transmembrane domain protein, blue in diagram).
  • Heterotrimeric G-protein (α, β, γ subunits; red in diagram).
  • Membrane enzyme/effector (e.g., adenylyl cyclase, phospholipase C).
• Nucleotide exchange:
  • Resting state: α-subunit bound to GDP.
  • Activation: ligand → receptor → α swaps GDP for GTP ( GDP + P_i \rightarrow GTP ) ➜ high-energy GTP drives dissociation & effector activation.
• Downstream possibilities ("signal transduction cascade"):
  1. Adenylyl cyclase path: ATP \rightarrow cAMP + PP_i; cAMP serves as a second messenger, activating protein kinase A and amplifying signal.
  2. Phospholipase C path: generates IP3 & DAG; IP3 releases intracellular Ca^{2+} (another second messenger).
  3. Direct channel modulation: G-protein βγ subunits or released Ca^{2+} open/close ion channels (e.g., sodium channels) → depolarization.
• Key properties: vast diversity, amplification, slower onset vs. LGICs but longer-lasting & versatile.

Named Receptor Families & Their Ligands

• Cholinergic receptors (bind Acetylcholine)
  • Nicotinic (nAChR) – LGIC type.
  • Muscarinic (mAChR) – GPCR type.
• Adrenergic receptors (bind Norepinephrine & Epinephrine)
  • Two principal GPCR sub-families:
  • \alpha-adrenergic (multiple subtypes: \alpha1, \alpha2, etc.)
  • \beta-adrenergic (subtypes \beta1, \beta2, \beta_3)
  • Physiologic example: NE binding \beta_1 on myocardium ➜ ↑ heart rate & ↑ ventricular contractility.

Agonists & Antagonists

• Agonist: exogenous or endogenous molecule that binds receptor & mimics native ligand ➜ full downstream effect.
• Antagonist: binds receptor but blocks downstream effect; no intrinsic activity.
• Clinical/toxicology notes:
  • Pharmaceuticals can be agonists (e.g., inhaled \beta_2 agonists for asthma) or antagonists (e.g., \beta-blockers).
  • Pathogens/toxins (cholera, botulism) often impair GPCR signaling, causing disease.

Receptor Dynamics: Saturation, Up- & Down-Regulation

• Saturation
  • Definition: all receptor binding sites occupied; adding more ligand produces no additional effect.
  • Even simple cells may possess 10^3 - 10^5 receptors for a single ligand.
• Up-regulation (increase receptor number/availability)
  • Trigger: chronically low ligand levels or high metabolic demand.
  • Examples:
  • Exercise ➜ skeletal muscle inserts more insulin receptors and more GLUT-4 glucose channels, heightening glucose uptake capacity.
  • Developmental stages requiring heightened growth factor sensitivity.
• Down-regulation (decrease receptor number or sensitivity)
  • Trigger: chronically high ligand concentration; cell protects itself from overstimulation.
  • Pathophysiologic highlight: Type 2 Diabetes Mellitus
  • Overeating/sedentary lifestyle ➜ hyperglycemia ➜ hyperinsulinemia.
  • Insulin-dependent tissues remove insulin receptors = insulin resistance.
  • Parallel desensitization: receptor conformation alters, further dampening response.

Blood-Brain Barrier (BBB) & Glucose Transport

• BBB endothelium expresses dedicated glucose transporters.
• Chronic hyperglycemia (diabetes) ➜ BBB down-regulates these transporters.
  • Protective vs. glucose overload but dangerous during hypoglycemic episodes.
  • Low serum glucose + fewer transporters → inadequate cerebral glucose ➜ altered mentation, loss of consciousness; requires rapid glucose administration.

Polar vs. Non-Polar Signal Molecules – Practical Takeaway

• Polar (hydrophilic / lipophobic)
  • Cannot cross lipid bilayer unaided.
  • Use membrane receptors (LGICs, GPCRs, enzyme-linked receptors).
  • Examples: ACh, NE, insulin, peptide hormones.
• Non-Polar (hydrophobic / lipophilic)
  • Freely diffuse through membrane.
  • Receptors in cytosol or nucleus; often directly regulate gene transcription.
  • Examples: steroid hormones (cortisol, estrogen), thyroid hormones, nitric oxide.

Cascade Amplification & Second Messengers

• GPCR pathways amplify signals: one ligand → many cAMP molecules → thousands of kinase targets.
• Classic second messengers: cAMP, cGMP, IP_3, DAG, Ca^{2+}, nitric oxide.
• Amplification yields high sensitivity; tiny extracellular changes produce robust intracellular outcomes.

Ethical / Pharmacological / Clinical Implications

• Selective agonists/antagonists exploit receptor specificity to treat disease with minimal off-target effects.
• Understanding receptor regulation underpins strategies for metabolic syndrome, heart failure, asthma, neurodegenerative diseases.
• Pathogens leveraging receptors (cholera toxin on GPCRs) illustrate evolutionary “arms race” & inform vaccine/antitoxin design.

Quick Reference Equations

• Nucleotide activation: GDP + P_i \rightarrow GTP (energy charge gained)
• Adenylyl cyclase reaction: ATP \rightarrow cAMP + PP_i
• Depolarization concept: \Delta Vm \approx +Na^+\ \text{influx} \Rightarrow Vm \text{ moves toward } 0\, \text{mV}

Interconnections to Previous & Future Lectures

• Links to earlier content:
  • ACh synthesis & synaptic release mechanism.
  • Insulin secretion from pancreatic β-cells (voltage-gated Ca^{2+} involvement following depolarization).
• Foundation for upcoming endocrine system discussions: hormone transport, receptor locations, and intracellular gene regulation.

Summary

• Signaling requires specific receptors; two central classes reviewed: LGICs (fast, direct ion flow) & GPCRs (versatile, amplified cascades).
• Receptor behavior (activation, regulation, pharmacologic modulation) is central to physiology, pathology, and therapeutics.