Lecture 8

Lecture 8: Chemical Messengers

Key Terms

• Paracrines: local messengers that affect neighboring cells

• Autocrines: chemical messengers that act on the same cell that secreted them

• Neurotransmitters: chemicals released from neurons to transmit signals to adjacent cells

• Hormones: long-distance messengers released into the bloodstream affecting distant cells

• Amino Acid Messengers: neurotransmitter molecules derived from amino acids

• Amine Messengers: derived from amino acids, often including hormones and neurotransmitters

• Peptide/Protein Messengers: consist of chains of amino acids, often functioning as hormones

• Steroid Messengers: lipid-soluble hormones derived from cholesterol

• Eicosanoid Messengers: derived from fatty acids, involved in inflammation and immune responses

• Specificity: the ability of a receptor to recognize and bind specific ligands

• Affinity: the strength of binding between a receptor and its ligand

• Saturation: the proportion of receptors that are bound by ligands

• Up-regulation: increase in receptor numbers or affinity in response to low messenger concentration

• Channel-Linked Receptors: facilitate fast synaptic transmission via ion channels

• Enzyme-Linked Receptors: act as enzymes when activated by ligands

• G Protein-Linked Receptors: activate G proteins and initiate intracellular signaling cascades

• Ligand-Gated Channels: ion channels that open in response to ligand binding

• Fast Ligand-Gated Channels: receptors that are also ion channels

• Slow Ligand-Gated Channels: receptors that are separate from ion channels

• Amplifier Enzyme: enzymes that amplify the signal from a single messenger molecule.

Direct Communication via Gap Junctions

• Connexons: structures that form gap junctions, allowing small molecules and ions to pass between neighboring cells.

• Examples:

  • Muscle cells in cardiac and smooth muscle allow synchronized contraction due to direct communication

  • Neurons and some glands in the brain and retina facilitate synchronized activities.

Indirect Communication via Chemical Messengers

• Process:

  • Chemical messengers are released into interstitial fluid (secretions).

  • These chemicals bind to receptors on target cells, either on the cell surface or internally.

  • The binding initiates a response through mechanisms called signal transduction.

• The effectiveness of the response generally correlates with the number of receptors bound by the messenger.

Chemical Messengers: Functional Classifications

(a) Paracrines

• Act on neighboring cells to induce a response.

  • Growth Factors: proteins promoting cell proliferation and differentiation.

  • Clotting Factors: proteins assisting blood clot formation.

  • Cytokines: peptides released from immune cells that coordinate the immune response.

(b) Neurotransmitters

• Released by presynaptic neurons at synapses, targeting postsynaptic neurons or cells.

(c) Hormones

• Released from endocrine glands into the bloodstream, affecting distant target cells.

• Neurohormones: specialized hormones released by neurosecretory cells similar to neurotransmitters.

Chemical Classification of Messengers

• Key Characteristic: ability to dissolve in plasma or cross the lipid bilayer of the plasma membrane.

  • Lipophilic (hydrophobic): lipid-soluble messengers, can cross membranes, do not dissolve well in plasma.

  • Lipophobic (hydrophilic): water-soluble messengers, cannot cross membranes but dissolve in plasma.

• Types of Messengers:

  • Amino acid messengers

  • Amine messengers

  • Peptide/protein messengers

  • Steroid messengers

  • Eicosanoid messengers

Detailed Classification of Chemical Messengers

1) Amino Acid Messengers

• Function predominantly as neurotransmitters within the brain and spinal cord.

• Must be synthesized in the neuron that secretes them.

• Classified as lipophobic (hydrophilic).

2) Amine Messengers

• Derivatives of amino acids, synthesized in secretory cells.

• Most classified as lipophobic (hydrophilic).

• Can function as paracrines, neurotransmitters, or hormones.

3) Peptide/Protein Messengers

• Predominantly polypeptides consisting of 3-100 amino acids.

• Lipophobic (hydrophilic).

• Functions include paracrines, neurotransmitters, and hormones.

4) Steroid Messengers

• Lipophilic (hydrophobic), able to cross plasma membranes.

• Cannot be stored in cells and are synthesized on demand.

• Primarily classified as hormones.

5) Eicosanoid Messengers

• Produced by nearly all body cells and synthesized on demand.

• Lipophilic (hydrophobic).

• Function primarily as paracrines, may be involved in pain and inflammatory responses.

Transport of Messengers

• Hormones are secreted and transported in the bloodstream, either dissolved or bound to carrier proteins.

• Free hormones leave the blood to bind to target cells; as they exit, more hormones are released from carrier proteins.

Signal Transduction Receptor Properties

• Specificity: receptors bind only specific ligands or classes of ligands.

• A single messenger can bind to multiple receptor types with varying affinities.

Signal Transduction (ST)

• A multistep pathway that converts signals from one form to another.

• Factors influencing target cell response:

  1. Messenger concentration

  2. Number of receptors present

  3. Affinity of receptors for the messenger.

1) Messenger Concentration

• Target cell response increases with messenger concentration.

• Saturation: all available receptors being bound by messengers indicates maximal response.

2) Number of Receptors

• Can vary under diverse conditions due to the synthesis and turnover of receptors.

• Up-regulation: increasing numbers of receptors in response to prolonged low messenger concentration.

  • Example: Hypothyroidism adaptation where increased synthetic hormones decrease receptor numbers safely.

3) Affinity of Receptors

• Receptors with higher affinity are more likely to bind the messenger at a given concentration.

Signal Transduction Mechanisms: Properties of Receptors

• Agonists and Antagonists:

  • Agonist: a ligand that binds to a receptor and produces a biological response.

  • Antagonist: a ligand that binds but does not initiate any response; may inhibit agonists.

Signal Transduction Mechanisms: Responses Mediated by Receptors

Intracellular Receptors

• For lipophilic messengers located in cytosol or nucleus.

• Binding may alter protein synthesis taking hours to days for effects to manifest.

Membrane-Bound Receptors

• Lipophobic messengers cannot cross the plasma membrane and rely on external receptor binding, which faces intracellular fluid.

• Types of membrane-bound receptors:

  1. Channel-linked receptors

  2. Enzyme-linked receptors

  3. G protein-linked receptors

Channel-Linked Receptors

• Determine ion permeability via presence of specific ion channels.

• Ligand-gated channels: open in response to chemical binding.

  • Fast ligand-gated channels: the receptor and channel are the same protein.

  • Slow ligand-gated channels: receptor and channel are separate.

Enzyme-Linked Receptors

• Receptor and enzyme are the same protein with the binding site facing interstitial fluid and active sites facing cytosol. Activation occurs via binding at the receptor.

G Protein-Linked Receptors

• Activate intracellular G proteins acting as links between receptors and membrane proteins; effectors can include ion channels or enzymes.

Second Messenger Systems

• G proteins catalyze the production of intracellular second messengers such as cyclic AMP (cAMP) from adenylate cyclase.

Phosphatidylinositol Second Messenger System - PIP2

• In involves phospholipase C converting PIP2 to DAG and IP3, influencing various intracellular responses.

Signal Amplification by Second Messengers

• One messenger binds to a receptor activating several G proteins.

• Each activated G protein boosts cAMP production, leading to substantial amplification of the signal at downstream targets.