Cell Signaling

G-PROTEIN-COUPLED RECEPTORS

Triggered by calcium ion release…

  • muscle contraction

  • Fertilized egg development

  • Secretion of neurotransmitters

Calcium ions do not drive the propagation of an action potential along a nerve axon → flow of sodium ions into the cell is primarily responsible for neuron action potentials

Bacterial toxins & Disease

Cholera → activates a G protein that stimulates adenylyl cyclase

Whooping couch (pertussis toxin) → inactivates a G protein that inhibits the cyclase

Both toxins ultimately activate adenylyl cyclase

ENZYME-COUPLED RECEPTORS

Mechanisms used to terminate a signal transmitted by activated RTKs…

  • The RTKs are internalized and digested in lysosomes

  • Activated receptors can be switched off by removal of their activating phosphates by a tyrosine phosphorylase

Ras Proteins

  • Mutations in Ras proteins are among the most common molecular changes seen in human cancers

  • Mutations cause Ras to be unable to hydrolyze its bound GTP to GDP

  • Ras proteins with this mutation can no longer turn themselves off

Essential Concepts

Cells communicate through extracellular chemical signals

  • Hormones carried in blood to distant target cells

  • Neighboring cells communicate through direct cell-cell contact

  • Extracellular signal molecules…

    • Must interact with receptor protein on or in a target cell (each receptor protein recognizes particular signal molecule)

    • Bind to cell-surface receptor proteins that convert (transducer) the extracellular signal into different intracellular signals (organized in signaling pathways)

Three main classes of cell-surface receptors:

  1. Ion-channel-coupled receptors

  2. G-Protein-Couple receptors

    • activate trimeric GTP-binding proteins called G proteins → molecular switches, transmitting the signal onward for a short period before switching themselves off by hydrolyzing GTP to GDP

    • G-proteins regulate ion channels or enzymes in plasma membrane

      • Directly activate (or inactivate) enzyme adenylyl cyclase, increasing (or decreasing) intracellular concentration of second messenger molecules, cyclic AMP

        • Rise in cyclic AMP activates cyclic-AMP-dependent protein kinase (PKA)

      • Directly activate enzyme phospholipase C, generating messenger molecules inositol triphosphate (IP3) and diaglycerol

        • IP3 opens Ca2+ channels in membrane of endoplasmic reticulum, releasing free Ca2+ into the cytosol → Ca2+ acts as second messenger, altering the activity of Ca2+-responsive proteins (ex. Calmodulin - CaM-kinases)

        • Ca2+ and diaglycerol in combination activate protein kinase C (PKC)

    • PKA, PKC, and CaM-kinases phosphorylate selected signaling and effector proteins on serines and threonine, altering their activity

    • Different cell types contain different sets of signaling and effector proteins and are affected in different ways

  3. Enzyme-coupled receptors

    • Intracellular protein domains that function as enzymes or are associated with intracellular enzymes

    • Many are receptor tyrosine kinases (RTKs): phosphorylate themselves and selected intracellular signaling proteins on tyrosines

    • Phosphotryosines on RTKs serve as docking sites for various intracellular signaling proteins

    • Most RTKs activate monomeric GTPase Ras, activating a three-protein MAP-kinase signaling module that helps relay signals from plasma membrane to nucleus

      • Ras mutations stimulate cell proliferation by keeping Ras (the Ras-MAP-kinase signaling pathway) constantly active

      • Common feature of many cancers

    • Some RTKs stimulate cell growth and survival by activating PI 3-kinase, which phosphorylate specific inositol phospholipids in the cytosolic leaflet of the plasma membrane lipid bilayer

    • Inositol phosphorylation creates lipid docking sites that attract specific signaling proteins from the cytosol (ex. Protein kinase Akt)

    • Notch receptors have a direct pathway to the nucleus → when activated, part of the receptor migrates from plasma membrane to the nucleus where it regulates the transcription of specific genes

    • Steroid hormones and nitric oxide → small or hydrophobic enough to cross plasma membrane and activate intracellular proteins

    • Plants use these to control their growth (often act by relieving transcriptional repression of specific genes)

    → GPCRs and enzyme-coupled receptors respond to extracellular signals by activating intracellular signaling pathways, which activates effector proteins that alter the behavior of the cell

    → Each activated component must be subsequently inactivated or removed for the pathway to function again

    → Different intracellular signaling pathways interact, enabling each cell type to produce the appropriate response to a combination of extracellular signals

    • in the absence of such signals, most animal cells have been programmed to kill themselves by undergoing apoptosis