Receptors and Signaling

Receptors

  • Sensing elements of chemical communication within the body
  • Respond to one (or more) signaling molecules due to ligand sensitivity
    • Common ECF, different responses

Ligand-gated ion channels

  • Location - plasma membrane
  • Hydrophilic signaling molecules
  • Millisecond timescale
  • Consist of separate glycoprotein subunits forming a central, ion conducting channel
  • Allow rapid changes in permeability of membrane to certain ions
  • Rapidly alter membrane potential

LGCI sequence of action

  1. Agonist binds - conformational change
  1. Channel opens - conduction pathway for ions
  1. Ions flow down electrochemical gradient
    1. Nicotinic ACh receptor → Na+ out + K+ in → membrane depolarization and excitation

G protein coupled receptors (GPCRs)

  • Location - plasma membrane
  • Hydrophobic signaling molecules
  • Second timescale
  • Receptor, G protein and effector are separate proteins
  • G protein couples receptor activation to effector modulation

Structure

Receptor
  • Integral membrane protein
  • Single polypeptide with extracellular NH2 terminal and intracellular COOH terminal
  • Contains 7 transmembrane ⍺-helical spans joined by 3 extracellular and 3 intracellular connecting loops
  • May sometimes function as dimers
G protein
  • Peripheral membrane protein
  • 3 polypeptide subunits (⍺, β, 𝛾)
  • G nucleotide binding site in ⍺ subunit that can hold GTP or GDP
  • Multiple types

How they work

No signaling:
  1. Receptor unoccupied
  1. ⍺ subunit binding site occupied by GDP
  1. Effector is not modulated
Turning signal on:
  1. Agonist activates receptor, causing a conformational change
  1. G protein couples with receptor
  1. ⍺ subunit releases GDP and GTP binds in its place (guanine nucleotide exchange)
  1. ⍺ subunit dissociates from receptor and β𝛾 dimer
    1. ⍺ subunit and β𝛾 dimer are both signaling units
  1. ⍺ subunit combines with effector and modifies its activity
  1. Agonist may dissociate from receptor but signaling can persist because G protein and receptor are now separate
Turning signal off:
  1. ⍺ subunit acts as an enzyme - hydrolyses GTP to GDP and Pi (signal is now off)
  1. ⍺ subunit recombines with β𝛾 subunit

Kinase-linked receptors

  • Location - plasma membrane
  • Hydrophilic protein mediators
  • Hour timescale
  • Example - insulin

Nuclear receptors

  • Location - nucleus or cytoplasm
  • Hydrophobic signaling molecules (steroid hormones)
  • Hours/day timescale
  • Ligand-gated transcription factors