Chemical Signaling by Neurotransmitters and Hormones

Foundations of Chemical Signaling in the Nervous System

  • Sequential Logic:

    • 1. Synthesis (MAKE): Transmitters synthesized via enzymes and packaged in vesicles.

    • 2. Release (RELEASE): Action potential triggers Ca2+\text{Ca}^{2+}-dependent exocytosis into synaptic cleft.

    • 3. Signal Transduction (SIGNAL): Transmitters bind ionotropic or metabotropic receptors.

    • 4. Signal Termination (STOP): Terminated via reuptake, enzymatic degradation, or diffusion.

    • 5. Plasticity & Adaptation (ADAPT): Synapses undergo structural and functional changes over time.

    • Core Principle: Drugs modify pre-existing physiological pathways rather than creating new ones.

  • Neural Circuit Organization:

    • Divergence: One presynaptic neuron projects to multiple targets.

    • Convergence: Multiple presynaptic neurons project onto a single target.

Electrical Activity, Ion Channels, and Membrane Potentials

  • Ion Channel Gating:

    • Ligand-Gated: Opens upon specific transmitter binding.

    • Voltage-Gated: Opens/closes in response to membrane potential shifts.

    • Phosphorylation-Gated: Regulated by protein kinase attachment of inorganic phosphate (PiP_i).

  • Membrane Potentials:

    • Resting Potential: Maintained at approximately −70 mV-70\,\text{mV}.

    • Local Potentials: Graded signals (Depolarization = less negative; Hyperpolarization = down to −100 mV-100\,\text{mV}).

    • Action Potential Threshold: Reaching −50 mV-50\,\text{mV} triggers an all-or-none spike up to +40 mV+40\,\text{mV}.

Synaptic Structure and Structural Classification

  • Anatomy: Presynaptic axon terminal (vesicles, mitochondria), Synaptic cleft, Postsynaptic dendritic spine, Astrocytic process.

  • Morphological Categories:

    • Axodendritic: Axon to dendrite/spine.

    • Axosomatic: Axon to cell body (soma).

    • Axoaxonic: Axon to axon terminal (mediates presynaptic inhibition/facilitation).

  • Neuromuscular Junction (NMJ): Motor terminal releases acetylcholine (ACh) onto sarcolemma junctional folds containing ACh receptors.

Neurotransmitter Identification Criteria and Functional Classes

  • Identification Criteria: Presynaptic synthesis, inactivation mechanism, stimulus-dependent release, postsynaptic receptors, exogenous mimicry, and pharmacological antagonism.

  • Classical Transmitters vs. Neuropeptides:

    • Classical Transmitters: Small molecules made in terminals, stored in small vesicles, fast local action (wiring transmission).

    • Neuropeptides: Synthesize+d in soma (RER/Golgi), transported in large dense-core vesicles via fast axonal transport, diffuse broadly (volume transmission).

  • Retrograde Messengers: Synthesized on-demand postsynaptically (e.g., gaseous NO\text{NO}, endocannabinoids) to act backwards on presynaptic terminals.

Classical Neurotransmission Step-by-Step

  • 10-Step Cascade:

    1. Transmitter synthesis & vesicular packaging.

    2. Action potential invades terminal.

    3. Voltage-gated Ca2+\text{Ca}^{2+} channels open.

    4. Ca2+\text{Ca}^{2+} influx into terminal.

    5. Vesicles fuse with presynaptic membrane.

    6. Exocytosis releases transmitter into cleft.

    7. Binding to postsynaptic receptors.

    8. Ion channels open or close.

    9. Postsynaptic potential (EPSP/IPSP) generated.

    10. Vesicle membrane retrieved via endocytosis.

Synaptic Vesicle Dynamics and Recycling

  • Vesicle Machinery: Synaptobrevin (v-SNARE) drives membrane fusion; vesicular transporters load transmitters.

  • Vesicle Lifecycle: Filling →\rightarrow Docking/Priming →\rightarrow Fusion/Exocytosis →\rightarrow Endocytosis.

  • Endocytic Pathways:

    • Clathrin-Mediated: Full fusion; slow retrieval (15–20 s15\text{--}20\,\text{s}).

    • Ultrafast: Rapid lateral retrieval (100 ms100\,\text{ms}), endosomal fusion (1 s1\,\text{s}), and budding (3–5 s3\text{--}5\,\text{s}).

    • Kiss-and-Run: Transient pore formation (1–2 s1\text{--}2\,\text{s}).

Neurotransmitter Release Regulation

  • Regulation Factors: Firing rate, exocytosis probability, autoreceptor feedback.

  • Autoreceptors:

    • Terminal Autoreceptors: On axon terminal; inhibit transmitter release.

    • Somatodendritic Autoreceptors: On soma/dendrites; hyperpolarize cell to reduce firing rate.

Signal Termination

  • Enzymatic Degradation: Enzymes break down transmitter in the cleft.

  • Presynaptic Reuptake: Active Na+\text{Na}^+-coupled transporters move transmitter back into terminal.

  • Glial Reuptake: Astrocytes remove transmitter from extracellular space.

Receptor Classification, Structure, and Dynamics

  • General Property: Transduce signals across membranes via conformational shifts (do not transport molecules).

  • Ionotropic Receptors: Multimeric (4--5 subunits) central ion channel; fast signaling.

  • Metabotropic Receptors (GPCRs): Monomeric 7-transmembrane (7-TM7\text{-TM}) protein coupled to G proteins; slower signaling.

    • Effector Actions: Direct ion channel gating or effector enzyme modulation.

  • Allosteric Modulation: PAMs enhance and NAMs decrease receptor response to agonists without binding the orthosteric site.

Second-Messenger Systems and Signal Transduction

  • Major Cascades & Kinases:

    • cAMP System: Adenylyl cyclase →\rightarrow Protein Kinase A (PKA).

    • cGMP System: Regulated by NO\text{NO} →\rightarrow Protein Kinase G (PKG).

    • Phosphoinositide System: PLC →\rightarrow DAG & IP3\text{IP}_3 →\rightarrow Ca2+\text{Ca}^{2+} release →\rightarrow Protein Kinase C (PKC).

    • Ca2+\text{Ca}^{2+} System: Ca2+\text{Ca}^{2+} influx →\rightarrow CaMKII.

  • Amplification: Kinases phosphorylate target proteins to alter channel function and gene expression.

Synaptic Plasticity

  • Long-Term Potentiation (LTP): High-frequency activity →\rightarrow sustained Ca2+\text{Ca}^{2+} influx →\rightarrow persistent increase in synaptic strength.

  • MAPK Signaling Pathway: Growth Factor →\rightarrow Receptor Tyrosine Kinase →\rightarrow Raf (MKKK) →\rightarrow MEK (MKK) →\rightarrow ERK (MAPK) →\rightarrow Cytosolic targets & transcription factors (e.g., c-Myc).

Pharmacological Action Sites

  • 11 Action Sites: Precursor admin ($+$), Synthesis inhibition ($-$), Storage blockade ($-$), Release stimulation ($+$), Release inhibition ($-$), Postsynaptic agonism ($+$), Postsynaptic antagonism ($-$), Autoreceptor agonism ($-$), Autoreceptor antagonism ($+$), Enzyme inhibition ($+$), Reuptake blockade ($+$).

Comparative Neurochemistry and Endocrine Signaling

  • Neural vs. Endocrine: Neural is point-to-point and fast (ms\text{ms}); Endocrine releases hormones into bloodstream for widespread, sustained effects.

  • Hormone Receptors:

    • Cell Surface: Hydrophilic peptides bind GPCRs or Tyrosine Kinase Receptors.

    • Intracellular: Lipophilic steroids cross lipid membrane to bind intracellular receptors, regulating gene transcription.

  • Neuroendocrine Interactions:

    • CNS D2D_2 occupancy above 60%–80%60\%\text{--}80\% by antipsychotics elevates plasma prolactin above 20 ng/ml20\,\text{ng/ml}.

    • Sex Steroids: Estradiol modulates dopamine signaling and drug responses.