Chapter 5 – Chemical Messengers & Signal Transduction

Big Picture: Intercellular Communication

• Goal: move information from one cell to another (intercellular) so the target cell changes its behavior.

• Two broad signaling modes

  • Electrical (via direct ionic current)

  • Chemical (via ligand binding)

• 3 organ systems that depend heavily on chemical messengers

  • Nervous

  • Endocrine

  • Immune

Electrical Signaling (Gap Junctions)

• Gap junction = permanent channel linking adjacent cells ("24/7 tunnel")

  • Built from connexon proteins (trans-membrane hexamers).

  • Cytosols of the two cells are continuous ⟹ ions & small solutes pass freely.

• Advantages

  • Very fast; nearly instantaneous spread of action potential (AP).

• Disadvantages

  • No directionality (signal flows both ways, uncontrolled).

• Key physiological examples

  • Cardiomyocytes – AP in one cell spreads through heart ➜ synchronous contraction.

  • Single-unit smooth muscle (GI tract, uterus, etc.).

  • Certain gland cells & some neurons.

• Because of lack of directionality, electrical signaling is a minority solution; most control is chemical.

Chemical Signaling – General Concepts

• Requires both:

  1. Ligand (a.k.a. chemical messenger)

  2. Receptor (highly specific, lock-and-key; binding is reversible & non-covalent)

• Directionality is built-in: ligand diffuses/flows toward target; only receptor-bearing cells respond.

• Once message delivered, ligand must be inactivated/removed so new signals can be recognized.

• Synonyms for ligand by organ system

  • Nervous → Neurotransmitter (NT)

  • Endocrine → Hormone

  • Immune → Cytokine

• Functional distance classes

  • Paracrine – short-range diffusion to neighboring cell.

  • Autocrine – ligand feeds back on cell that secreted it.

  • Hormone – secreted into blood; long-distance.

  • Note: some cytokines behave as paracrine and endocrine messengers.

Solubility Dictates Receptor Location

• Water-soluble / hydrophilic / lipophobic

  • Cannot cross lipid bilayer.

  • Receptor must be integral plasma-membrane protein.

• Lipid-soluble / lipophilic / hydrophobic

  • Diffuse through membranes.

  • Receptors are intracellular (cytosol or nucleus).

  • Ligand–receptor complex often acts as a transcription factor (TF) called a Hormone Response Element (HRE).

Functional Classification of Chemical Messengers

1. Neurotransmitters (NTs)

   • Released by presynaptic neuron into microscopic space.

   • Spaces & proper terminology

     • Neuron → neuron: Synapse (pre- & post-synaptic neurons)

     • Neuron → gland: Neuroglandular junction

     • Neuron → skeletal muscle fiber: Neuromuscular junction

   • Messenger is always a neurotransmitter regardless of the effector type.

2. Hormones (Endocrine)

   • Secreted by endocrine cells → blood (vascular bed) → distant targets.

   • Typical examples

     • Insulin (β-pancreatic cells) – regulates plasma glucose uptake.

     • ADH / Vasopressin (hypothalamus → posterior pituitary) – water reabsorption in kidneys.

3. Cytokines (Immune)

   • May act locally (paracrine) or systemically (endocrine). Examples: interleukins, interferons.

4. Paracrine / Autocrine Factors

   • Growth factors, clotting factors, many cytokines.

Structural / Chemical Classification

• Amino-acid derivatives (e.g., glutamate, GABA, epinephrine)

• Peptides & Proteins (largest group)

  • Convention used in this course

  • $1\text{–}99$ aa = peptide

  • $\ge 100$ aa = protein/polypeptide

  • Synthesized on RER as pre-pro-hormone → pro-hormone → active hormone

  • Example: Parathyroid Hormone (PTH)

    • Pre-pro-PTH (115 aa) → Pro-PTH (90 aa) → Active PTH (84 aa)

    • Secreted via Golgi vesicles → exocytosis.

• Steroids (cholesterol-derived; lipophilic)

• Eicosanoids (arachidonic-acid derived; lipophilic)

• Purines, gases, etc. (minor classes)

(Table 5.1–5.6 summarize properties; ALL are testable.)

Signaling Cascades – Overview

• Signal transduction = cascade converting extracellular message → intracellular response.

• Three major plasma-membrane receptor families for hydrophilic ligands

  1. Ligand-gated ion channels (ionotropic)

  • Binding opens/closes pore → ionic influx/efflux (facilitated diffusion).

  • Example: $\text{Ca}^{2+}$ influx triggers secretion, contraction, or changes in Vm.

  1. Enzyme-linked receptors (e.g., Receptor Tyrosine Kinase, RTK)

  • Ligand binding → receptor’s intrinsic kinase phosphorylates specific tyrosines on target proteins.

  • Prototype: Insulin receptor.

  1. G-Protein–Coupled Receptors (GPCR / G-protein–linked)

  • 7-TM receptor activates heterotrimeric G-protein (focus on α-subunit).

    • Gα can

      • Directly gate an ion channel (indirect channel regulation).

      • Stimulate or inhibit membrane enzymes that generate second messengers.

Major Second Messengers (Table 5.3, p.141)

1. $\text{Ca}^{2+}$ (ionic)

2. cAMP (cyclic adenosine monophosphate)

3. cGMP (cyclic guanosine monophosphate)

4. IP$_3$ (inositol $1,4,5$-trisphosphate)

5. DAG (diacylglycerol)

Classic GPCR ➜ cAMP Pathway (Fig 5-19)

• Ligand → GPCR → Gα_s activates adenylyl cyclase (AC).

• AC converts $\text{ATP} \to \text{cAMP}$.

• cAMP activates Protein Kinase A (PKA).

• PKA phosphorylates many substrates → cellular response.

• Signal Amplification

  • 1 ligand → many $Gα$ → many AC → tens of thousands cAMP → many PKA → millions of phosphorylated proteins.

Lipophilic Messenger Pathway

• Messenger diffuses through membrane & nuclear envelope.

• Binds intracellular receptor → forms hormone-receptor complex.

• Complex binds DNA at HRE → acts as transcription factor.

  • ↑ or ↓ transcription (gene-specific).

  • Alters mRNA levels → protein synthesis → long-term effects.

• Potency/Danger

  • Can globally alter cell phenotype or cause cell death if critical proteins suppressed.

  • Many toxins & lipid-soluble drugs exploit this access.

Ion Flux Terminology (used throughout course)

• Influx = movement into cytosol (e.g., $\text{Na}^+$, $\text{Ca}^{2+}$, $\text{Cl}^-$ via open channels).

• Efflux = movement out of cytosol (e.g., $\text{K}^+$ through open channels).

• Both forms here are passive transport / facilitated diffusion (no ATP, driven by electro-chemical gradient).

Representative Physiological Stories (Integrative Reminders)

• Insulin (peptide, water-soluble)

  • Binds RTK on systemic cells → kinase cascade → translocation of GLUT-4 → glucose uptake, lowers plasma glucose.

• ADH / Vasopressin (peptide, water-soluble; neurohormone)

  • Binds V2 GPCR on renal collecting-duct cells → cAMP/PKA → insertion of aquaporin-2 → water reabsorption when dehydrated.

• PTH (peptide, water-soluble)

  • Released when plasma $\text{Ca}^{2+}$ drops.

  • Acts on bone, kidney, and indirectly gut to restore $\text{Ca}^{2+}$ levels.

Key Vocabulary & Abbreviations

• Ligand = chemical messenger (NT, hormone, cytokine, etc.)

• Receptor = sensing protein (may be channel, enzyme, GPCR, or intracellular TF).

• TMP = Trans-membrane protein.

• GPCR = G-protein–coupled receptor.

• RTK = Receptor tyrosine kinase.

• HRE = Hormone response element.

• TF = Transcription factor.

• cAMP = $\text{3',5'}$-cyclic adenosine monophosphate.

• cGMP = $\text{3',5'}$-cyclic guanosine monophosphate.

• IP$_3$ = Inositol $1,4,5$-trisphosphate.

• DAG = Diacylglycerol.

Study Checklist / Action Items

• Master Tables 5.1–5.6; know characteristics of every messenger class.

• Memorize the 5 major second messengers & their paired enzymes/receptors.

• Practice labeling synapse vs neuroglandular vs neuromuscular junction.

• Trace cAMP cascade start-to-finish; be able to annotate each amplification step.

• Correlate solubility → receptor location → molecular mechanism (hydrophilic vs lipophilic).

• Review calcium-dependent events (secretion, muscle contraction, membrane potential changes).

• Re-draw gap junction scheme & list all tissues that use it.

• Understand peptide hormone synthesis (pre-pro → pro → active) & secretion via exocytosis.