Cell Signaling Notes

Cell Signaling

Signal Transduction

  • Signal transduction is the process of converting a signal from one form into another.
  • Involves an extracellular signal molecule (A).
  • Which leads to an intracellular signaling molecule (B)

Primary Ways of Sending a Signal

  • There are four primary ways of sending a signal in multicellular organisms.
    1. A signaling molecule produced by the signaling cell:
      • Can be proteins, peptides, amino acids, nucleotides, steroids, fatty acids, dissolved gases.
    2. A receptor in the target cell:
      • Receptors are proteins.

Endocrine Signaling

  • Endocrine signaling is long-range broadcasting.
  • Signaling molecules are called hormones.
  • Endocrine cells produce and secrete hormones.
  • Hormones travel through the bloodstream (or sap in plants).
  • Any cell with the right receptor can respond.
Examples of Signal Molecules (Hormones):
  • Adrenaline (epinephrine):
    • Site of Origin: Adrenal gland
    • Chemical Nature: derivative of the amino acid tyrosine
    • Actions: increases blood pressure, heart rate, and metabolism
  • Cortisol:
    • Site of Origin: Adrenal gland
    • Chemical Nature: steroid (derivative of cholesterol)
    • Actions: affects metabolism of proteins, carbohydrates, and lipids in most tissues
  • Estradiol:
    • Site of Origin: Ovary
    • Chemical Nature: steroid (derivative of cholesterol)
    • Actions: induces and maintains secondary female sexual characteristics
  • Insulin:
    • Site of Origin: B cells of pancreas
    • Chemical Nature: protein
    • Actions: stimulates glucose uptake, protein synthesis, and lipid synthesis in various cell types
  • Testosterone:
    • Site of Origin: Testis
    • Chemical Nature: steroid (derivative of cholesterol)
    • Actions: induces and maintains secondary male sexual characteristics
  • Thyroid hormone (thyroxine):
    • Site of Origin: Thyroid gland
    • Chemical Nature: derivative of the amino acid tyrosine
    • Actions: stimulates metabolism in many cell types.

Paracrine Signaling

  • Paracrine signaling is local signaling.
  • Signal molecules act as local mediators on nearby cells.
  • Signals diffuse through extracellular fluid (does not involve the bloodstream).
  • Signals that regulate inflammation and wound healing act in a paracrine manner.
  • Cells can respond to the signals they have produced (autocrine signaling).
Examples of Signal Molecules (Local Mediators):
  • Epidermal growth factor (EGF):
    • Site of Origin: various cells
    • Chemical Nature: protein
    • Actions: stimulates epidermal and many other cell types to proliferate
  • Platelet-derived growth factor (PDGF):
    • Site of Origin: various cells, including blood platelets
    • Chemical Nature: protein
    • Actions: stimulates many cell types to proliferate
  • Nerve growth factor (NGF):
    • Site of Origin: various innervated tissues
    • Chemical Nature: protein
    • Actions: promotes survival of certain classes of neurons; promotes their survival and growth of their axons
  • Histamine:
    • Site of Origin: mast cells
    • Chemical Nature: derivative of the amino acid histidine
    • Actions: causes blood vessels to dilate and become leaky, helping to cause inflammation.
  • Nitric oxide (NO):
    • Site of Origin: nerve cells; endothelial cells lining blood vessels
    • Chemical Nature: dissolved gas
    • Actions: causes smooth muscle cells to relax; regulates nerve-cell activity

Neuronal Signaling

  • Neuronal signaling is long range, targeted signaling.
  • An activated neuron first sends an electrical signal down its axon.
    • Makes this type of signaling extremely fast.
  • The electrical impulse triggers release of neurotransmitter at the synapse.
  • The axon terminal at the synapse is very close to a target cell.
    • Gives specificity to the signaling.
Examples of Neurotransmitters:
  • Acetylcholine:
    • Source: nerve terminals
    • Chemical Nature: derivative of choline
    • Action: excitatory neurotransmitter at many nerve-muscle synapses and in central nervous system
  • Y-Aminobutyric acid (GABA):
    • Source: nerve terminals
    • Chemical Nature: derivative of the amino acid glutamic acid
    • Action: inhibitory neurotransmitter in central nervous system

Contact-Dependent Signaling

  • Contact-dependent signaling is very short-range cell to cell communication.
  • Neighboring cells make direct physical contact.
  • Both the receptor and the signaling molecule are membrane-bound.
Delta-Notch Signaling
  • Delta-Notch signaling is critical for development.
  • Delta:
    • Source: prospective neurons; various other developing cell types
    • Nature : transmembrane protein
    • Action: inhibits neighboring cells from becoming specialized in the same way as the signaling cell

Cell Response to Signals

  • Each cell responds to a limited set of extracellular signals.
  • A cell must have the correct receptor to respond to the signal.
    • Each receptor typically responds to only one type of signal.
  • Signal transduction depends on intracellular signaling molecules and effector proteins.
    • Each cell has a unique set of intracellular signals and effectors.
  • A typical cell is exposed to hundreds of signals in the bloodstream, extracellular fluid, and neighboring cells.
Examples of Cell-Specific Responses:
  • Heart pacemaker cell: Acetylcholine leads to DECREASED RATE OF FIRING.
  • Salivary gland cell: Acetylcholine leads to SECRETION.
  • Skeletal muscle cell: Acetylcholine leads to CONTRACTION.

Combination of Signals

  • The combination of signals received by the cell dictates the cell's response.
  • Examples of possible cell responses:
    • SURVIVE
    • GROW + DIVIDE
    • DIFFERENTIATE
    • DIE (undergoing apoptosis)

Speed of Intracellular Response

  • The intracellular response to an extracellular signal can be fast or slow.
  • Determined by the intracellular signaling pathway(s) activated.
  • A fast response involves altered protein function.
  • A slow response involves altered transcription/translation.
  • Signals may activate pathways that act in both ways.

Extracellular and Intracellular Receptors

  • Extracellular signaling molecules bind to cell surface receptors or intracellular receptors.
    • Cell surface receptors: Signal cannot cross the cell membrane.
    • Intracellular receptors: Signal can pass through the cell membrane.

Steroid Hormones

  • Steroid hormones bind intracellular receptors.

  • Examples:

    • Cortisol
    • Estradiol
    • Testosterone
    • Thyroxine

  • Characteristics:

    • Relatively small
    • Relatively hydrophobic
    • Can pass through the cell membrane

  • The receptor for cortisol is also the effector protein (common among intracellular receptors).

Nitric Oxide (NO)

  • Nitric oxide is a nonpolar gas that can diffuse through the cell membrane.
  • Endothelial cells in blood vessels are stimulated by acetylcholine to produce NO.
  • NO diffuses into neighboring smooth muscle cells and causes them to relax.
  • NO signaling leads to local increased blood flow.

Transmembrane Protein

  • Extracellular signals that cannot cross the cell membrane must bind and activate a cell surface receptor.
  • The cell surface receptor is a transmembrane protein.
  • Signals are relayed by intracellular signaling pathways.
  • Intracellular signaling can activate many types of effector proteins.

Crucial Functions of Intracellular Signaling Pathways

  • Relay: Pass the signal on.
  • Amplify: Turn one message into many via second messengers.
  • Integrate: Detect signals from multiple pathways before relaying a message.
  • Distribute: Regulate one or more effector proteins.

ATP and GTP in Intracellular Signaling

  • ATP and GTP are critical components of intracellular signaling.
  • Phosphorylation is a covalent protein modification.
  • Kinases phosphorylate other proteins.
  • Phosphatases remove phosphorylations.
  • A signal could activate either a kinase or a phosphatase.
  • GTP-binding proteins (GTPases) are regulated allosterically.
    • GTP and GDP bind through noncovalent interactions.
  • Proteins are made active or inactive depending on whether they are bound to GTP or GDP.

GEFs and GAPs

  • The signals that regulate GTPases are activated GEFs and GAPs.
  • GEF (Guanine Exchange Factor):
    • Promotes swap of GDP for GTP.
  • GAP (GTPase Activating Protein):
    • Stimulates hydrolysis of the bound GTP.

Major Classes of Membrane Receptors

  • Ion-channel-coupled receptors
  • G-protein-coupled receptors
  • Enzyme-coupled receptors