Cell-to-Cell Communication Notes

Direct Communication Through Gap Junctions

  • Gap junctions – Channels formed between two cells via connexons

  • Membrane proteins – Direct electrical and metabolic coupling

  • Common in smooth and cardiac muscle, and other cells

Indirect Communication Through Chemical Messengers

  • Indirect Communication Through Chemical Messengers

    • Secretory cell → Chemical messenger → Receptor (b) communication via chemical messengers

    • Target cell = Receptor protein; may be membrane protein or cytoplasmic protein

    • (Figure 5.1b referenced)

Classification of Chemical Messengers

  • Mode of Action:

    • Autocrines

    • Paracrines

    • Endocrine

  • Functional Class:

    • Hormones (Endocrine)

    • Neurotransmitters/Neurohormones

    • Cytokines

  • Two ways to classify messengers:

    • By mode of action (autocrine, paracrine, endocrine)

    • By functional class (hormones, neurotransmitters/neurohormones, cytokines)

Autocrines

  • Autocrines act on cells that release them

  • Mechanism:

    • Autocrine secretory cell → receptor on same cell

  • (Figure 5.2b illustrative)

Paracrines

  • Paracrines are released by secretory cell and move to nearby target cells by diffusion

  • Act on neighboring cells

  • Example: Histamine – released with tissue damage and causes dilation of local blood vessels

  • (Figure 5.2a)

Endocrine (Hormonal) Signaling

  • Messenger of the endocrine system = hormones

  • Released from an endocrine gland into blood

  • Transported in blood to target tissues

  • Target cells are those with receptors specific to the hormone

  • (Figure 5.2d)

Neurotransmitters

  • Messenger of the nervous system

  • Released from a neuron by exocytosis

  • Diffuses to a very close target cell

  • (Figure 5.2b)

Neurohormones

  • Messenger = neurohormone

  • Released from specialized secretory neurons into blood

  • Acts in a manner similar to hormones

  • (Figure 5.2e)

Cytokines

  • Cytokines = peptides or proteins

  • Can be transported in blood; most act on neighboring cells (paracrines)

  • Released by most cell types

  • Involved in cell development, cell differentiation, and immune response

  • Often act on a wide range of targets

  • (Figure 5.2f)

Signal Transduction Mechanisms

  • Process by which messenger binding to receptor produces response in target cell

  • Receptors = proteins with specific binding sites for messengers

  • Note: most receptors (R) are specific for one type of messenger (M)

Receptor Specificity

  • Receptor C binds Messenger 1; Receptor A binds Messenger 1; Receptor B binds Messenger 2

  • Target cell for messenger 1: Receptor A

  • Target cell for messenger 2: Receptor B

  • (Figure 5.8 illustration)

Magnitude of Response of Target Cell to Messenger

  • Magnitude depends on the number of receptors bound by the messenger

  • Depends on three factors:

    • Concentration of messenger

    • Number of receptors present on the target cell

    • Affinity of receptor for messenger (binding strength)

  • Diagrammatic representation: M + R ⇄ M bound to R → Response

  • Mathematical sketch: M+R⟶M bound to R⟶ResponseM + R \longrightarrow M\text{ bound to }R \longrightarrow \text{Response}

Up- and Down-Regulation of Receptors

  • Down Regulation: occurs when excess messenger is present

    • Target cell decreases number of receptors for messenger

    • Leads to tolerance

  • Up Regulation: occurs when too little messenger is present

    • Target cell increases number of receptors for messenger

    • Leads to hypersensitivity

Receptor Agonists and Antagonists

  • Agonist: binds to a receptor and mimics normal response

  • Antagonist: binds to a receptor and produces no response

  • Antagonists compete with the normal messenger

Example: Receptor Agonists and Antagonists

  • Beta-endorphin = endogenous opiate

    • Binds to opiate receptors → analgesia (pain reduction)

  • Morphine = opiate receptor agonist

    • Administration → analgesia

  • Naloxone = opiate receptor antagonist

    • Blocks opiate action → antidote for morphine/heroin overdose

Signal Transduction Mechanisms – Cont.

  • Intracellular Receptor-Mediated Responses

    • Messenger must diffuse into the cell (lipid-soluble)

    • Receptor can be in cytoplasm or nucleus

    • Alters protein synthesis

    • Receptor–messenger (RM) complex travels to the nucleus

  • Membrane Receptor-Mediated Responses

    • Channel-linked Receptors

    • Enzyme-linked Receptors

    • G-Protein-linked Receptors

    • Signal amplification via G protein – many intracellular regulatory proteins can be affected by a few extracellular messengers

1. Channel-Linked Receptors

  • Receptors that open/close ion channels in response to messenger binding

  • Also called Ligand (chemical) gated ion channels

Ligand-gated Channels

  • Ligand-gated channels open or close in response to binding of ligand to receptor

  • Ligand = messenger that binds to receptor/channel

  • Open channels correspond to increased permeability (diffusion of ions)

  • Two main categories:

    • Fast channels: receptor and channel are the same protein

    • Slow channels: receptor coupled to channel by G protein (discussed later with G-protein linked receptors)

Fast Ligand-Gated Channels for Na+, K+, and/or Cl-

  • Effect: Changes electrical properties of cell

  • Layout: Extracellular messenger → receptor and ion channel → cytosol

  • Diagrammatic summary: Channel closed; ions move through open channel; changes in electrical properties

2. Enzyme-Linked Receptors

  • Two main categories:

    • Receptor and enzyme are the same protein

    • Receptor linked to enzyme (by G protein in membrane, discussed next)

Enzyme-Linked Receptors – Cont.

  • Receptor and enzyme = same protein, usually a transmembrane protein

  • Example: Tyrosine kinase – an enzyme that adds a phosphate group to certain tyrosine amino acids in regulatory proteins, causing altered response in the cell

  • (Figure 5.13 reference)

3. G Protein Linked Receptors

  • Binding of extracellular messenger changes activity of a G protein that functions as a coupler (linker)

  • G proteins = regulatory proteins in membranes

  • They link the extracellular messenger to an amplifier enzyme or ion channel

  • G protein = “GTP binding protein”; GTP = guanosine triphosphate

Actions of G Proteins

  • Messenger binds receptor → extracellular signal

  • Receptor activates G protein

  • G protein acts as regulator for downstream effector (ion channel or enzyme)

  • Cycle: GDP ↔ GTP transitions drive the on/off state

  • Diagrammatic representation:

    • Receptor → G protein (GDP bound inactive) → GTP bound active → Regulated protein (ion channel or enzyme) → Cytosol → Response in cell

  • Stepwise labels often shown as: GDP → GTP activation, with subsequent downstream effects

G Proteins and Slow Ligand-Gated Ion Channels

  • G proteins can couple extracellular messengers to ion channels that alter electrical properties of the cell

  • Mechanism involves GTP/GDP cycling and channel modulation

  • (Figure 5.15 reference)

G Protein-Regulated Enzymes

  • Messenger → Receptor → G protein → Substrate → Amplifier enzyme → Second messenger → Activates protein kinase → Response in cell

  • Many regulatory proteins can be activated; this yields signal amplification

  • Pathway illustrated as: Substrate → Enzyme → Second messenger → Activation of kinases → broad cellular response

  • Diagrammatic steps (Figure 5.16):
    1) Messenger binds receptor
    2) Activation of G protein (GDP → GTP)
    3) G protein activates an amplifier enzyme
    4) Amplifier enzyme generates a second messenger
    5) Second messenger activates protein kinase(s) → Cellular response

Termination of Message

  • Mechanisms to terminate signaling:

    • Enzymatic degradation of messenger

    • Diffusion of messenger away from receptor

    • Internalization of messenger–receptor complex