Peptide neurotransmission

Neurotransmission I: Peptides

Presenter: Christopher D Schmoutz, PhDContact: christopher.schmoutz@lsuhs.eduLocation: Room 5-211

Goals and Learning Objectives

Overview: Understand details of neuropeptide biosynthesis and signaling mechanisms.

Learning Objectives:

  1. Compare and contrast small molecule and peptide neurotransmission.

    • Differences Between Small Molecule and Peptide Transmitters

    • Comparison Parameters:

      • Synthesis sites: Small molecule neurotransmitters are often synthesized in nerve terminals, while peptide neurotransmitters are synthesized in the cell body.

      • Axonal transport mechanisms: Small molecules can be rapidly transported down the axon, whereas peptides are transported via a slower mechanism.

      • Types and positioning of vesicles: Small molecules are stored in small synaptic vesicles; peptides are stored in large dense core vesicles.

      • Release mechanisms: Small molecules are released in response to local calcium influx, while peptides require larger calcium concentrations due to their storage further from synapses.

      • Reuptake processes: Small molecules generally have reuptake mechanisms; peptides are often degraded by peptidases instead of reuptake.

  2. Describe neuropeptide biosynthesis, processing, storage, and release.

    • Neuropeptide Biosynthesis Process:

      • Synthesis: Neuropeptides are synthesized on ribosomes in the endoplasmic reticulum (ER) of neurons.

      • Packaging: After synthesis, propeptides are packaged into large dense core vesicles, accompanied by processing enzymes.

        • [Image 1: Synthesis and Packaging Steps]

      • Processing: Concomitantly with packaging, propeptides are processed into their mature forms through enzymatic cleavage.

        • [Image 2: Processing Steps]

      • Release: The release of neuropeptides occurs upon high-frequency stimulation of neurons that trigger calcium influx, leading to vesicle exocytosis.

        • [Image 3: Release Mechanism]

  3. Identify examples of neuropeptides and their physiological roles.

    • Neuropeptides:

      • Definition: Neuropeptides are defined as short chains of amino acids, typically containing fewer than 50 amino acids.

      • Synthesis and Function:

        • Neuropeptides are synthesized, stored, and released effectively by various cells in the nervous system.

        • Upon release, they bind to substrate receptors on target cells, facilitating signaling in either a paracrine (local) or endocrine (systemic) manner.

        • Neuropeptides represent an ancient form of cellular signaling first observed in cnidarians, indicating their fundamental evolutionary significance.

        • A larger variety of bioactive peptides exists in the body than traditional neurotransmitters, suggesting a complex interplay in signaling processes.

        • The concept establishes that peptides act as important units of information in cellular communication.

Key Neuropeptides and Hormones

  • Neuropeptide Names and Functions:

    • CRH: Corticotropin-Releasing Hormone - involved in stress response.

    • GnRH: Gonadotropin-Releasing Hormone - critical for reproductive hormone regulation.

    • TRH: Thyrotropin-Releasing Hormone - stimulates thyroid function.

    • DA: Dopamine - key neurotransmitter involved in reward and motivation.

    • GHIH: Growth Hormone-Inhibitory Hormone - regulates growth hormone secretion.

    • ACTH: Adrenocorticotropic Hormone - stimulates cortisol production in adrenal glands.

    • FSH: Follicle Stimulating Hormone - essential for reproductive processes.

    • TSH: Thyroid Stimulating Hormone - regulates thyroid gland activity.

    • PRO: Prolactin - stimulates milk production.

    • LH: Luteinizing Hormone - triggers ovulation and testosterone production.

    • Other hormones also regulate functions of the pituitary, adrenal glands, and various tissues, reflecting the diverse physiological roles of neuropeptides.

Selected Bioactive Peptides

  • Categories:

    • Hypothalamic Releasing Factors: Examples include CRH, GHRH, GnRH, TRH, which facilitate the release of hormones from the pituitary gland.

    • Opiate Peptides: Include B-endorphin and Dynorphin, which are involved in pain modulation and the reward system.

    • Neurohypophyseal Peptides: Include Oxytocin and Vasopressin, hormones critical for social bonding and fluid regulation.

    • Pituitary Hormones: Include ACTH, PRL, which are produced by the anterior pituitary and influence numerous bodily functions.

    • GI and Pancreas Peptides: CCK, Ghrelin, and Gastrin are significant in digestion and metabolism regulation.

Finding Peptide Signals

  • Identification Methods:

    • Bioassays: Employ tests to identify which protein extracts stimulate specific biological responses, such as the isolation of Substance P.

    • Receptor-Based Assays: Utilize fraction extracts that can displace known ligand binding, confirming the presence of specific receptors for peptides.

    • Mass Spectrometry: Analyze peptide fragments, their structures, and the specificity for receptors.

      • Focus on Signature Characteristics:

        • Key molecular modifications such as COOH-terminal alpha-amidation or tyrosine sulfonation (as seen in Neuropeptide Y) play a pivotal role in functionality and signaling.

Peptide Processing and Regulation

  • Enzymatic Involvement:

    • Enzymes such as signal peptidase, prohormone convertases, carboxypeptidase E, and monoxygenases are involved in processing and enhancing peptide activity.

    • Timeline: The entire process of biosynthesis and subsequent processing may span several hours, often limited by the rate at which these enzymes operate.

    • Tissue-Specific Processing:

      • In the anterior pituitary, major production includes ACTH(1-39) and beta-lipotropin.

      • Arcuate neurons produce beta-endorphin and various ACTH forms.

Evolutionary Variations

  • Insights:

    • One precursor can lead to multiple bioactive peptides, showcasing the versatility of gene expression and processing.

    • Mechanisms such as alternative mRNA splicing and RNA editing significantly contribute to the diversity seen in peptide structures and functions.

Regulation of Peptide Expression

  • Mechanisms:

    • Transcription factor activity can modulate mRNA synthesis and splicing.

    • The responsiveness of ribosomes and the Endoplasmic Reticulum (ER) to mRNA influences the rates of translation, thereby impacting peptide availability and function.

Neuropeptide Comparison Chart

  • Key Differences:

    • Neuropeptides: Characterized by low concentration in circulation, high distribution across different cells and tissues, and a nanomolar binding affinity to their receptors.

    • Neurotransmitters: Present in high concentrations, exhibit lower distribution, and bind to receptors with micro- or millimolar affinities.

    • The biosynthesis locations and subsequent release conditions between the two classes vary significantly, reflecting their different physiological roles in the nervous system.