Signal transmission and signal transduction XIA Qiang, MD & PhD Department of Physiology Room 518, Block C, Research Building School of Medicine, Zijingang Campus Tel: (Undergraduate school), (Medical school)

OUTLINE  Intercellular signal transmission  Chemical transmission  Electrical transmission  Signal transduction pathway  Pathways initiated by intracellular receptors  Pathways initiated by plasma membrane receptors

Intercellular signal transmission  Chemical transmission  Chemical signals  Neurotransmitters:

Intercellular signal transmission  Chemical transmission  Chemical signals  Neurotransmitters:  Humoral factors:  Hormones  Cytokines  Bioactivators

Intercellular signal transmission  Chemical transmission  Chemical signals  Neurotransmitters:  Humoral factors:  Gas: NO, CO, etc.

Intercellular signal transmission  Chemical transmission  Chemical signals  Receptors  Membrane receptors  Intracellular receptors

Receptors on the surface of a cell are typically proteins that span the membrane

Cells B & C lack the matching receptors Therefore are not directly affected by the signal Only Cell A has the matching receptors for this chemical messenger, so it is the only one that responds

Intercellular signal transmission  Electrical transmission Gap junction

Low Magnification View The intercalated disk is made of several types of intercellular junctions. The gap junction provides a low resistance pathway for the action potential to spread from cell to cell Cardiac Muscle

Signal transduction pathway  Pathways initiated by intracellular receptors  Pathways initiated by plasma membrane receptors

… but at the target cell the signal moves easily through the membrane and binds to its receptor This hydrophobic signal requires a carrier protein while in the plasma …

Signal transduction pathway  Pathways initiated by intracellular receptors  Pathways initiated by plasma membrane receptors (transmembrane signal transduction)

Transmembrane signal transduction

 Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

Binding of ligands to membrane-spanning receptors activates diverse response mechanisms

 Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

The Nobel Prize in Physiology or Medicine 1994  "G-proteins and the role of these proteins in signal transduction in cells" Alfred G. GilmanMartin Rodbell

The Discovery of G Proteins Normal Lymphoma CellMutated Lymphoma Cell

Activation and Inactivation of the G Protein 1. The G protein, composed of alpha-, beta- and gamma-subunits, in its resting state with bound GDP. 2. The receptor with bound hormone activates the G protein and replaces GDP with GTP and the G proteins is activated. The subunits separate. 4. Some seconds later the GTP, bound to the alpha-subunit, is hydrolysed to GDP. The subunits recombine.

G-protein-coupled Receptors

Signaling molecules involved Second messenger G protein effector Protein kinase   

(1) cAMP-PKA pathway (2) IP 3 -Ca 2+ pathway (3) DG-PKC pathway (4) G protein-ion channel pathway Main signaling pathways

(1)cAMP-PKA pathway Gs, Gi

The cyclic AMP second messenger system

Adenylyl cyclase forms cAMP, a “second messenger” that activates enzymes used in cellular responses The phosphodiesterase enzymes “terminate” the second messenger cAMP

The cAMP system rapidly amplifies the response capacity of cells: here, one “first messenger” led to the formation of one million product molecules

Cells can respond via the cAMP pathways using a diversity of cAMP-dependent enzymes, channels, organelles, contractile filaments, ion pumps, and changes in gene expression

(2) IP 3 -Ca 2+ pathway: Gq (3) DG-PKC pathway: Gq PIP2: phospholipid phosphatidylinositol 4,5-bisphosphate DAG: diacylglycerol IP3: inositol 1,4,5-trisphosphate

This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP 3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels

Click here to play the Membrane Bound Receptors, G Proteins, and Calcium Channels Flash Animation

(4) G protein-ion channel pathway

Binding of the ligand to the receptor alters the receptor’s shape, which activates an associated G-protein, which then activates effector proteins, i.e., enzyme functions or ion channels

The calcium-calmodulin system is similar to some of the cAMP pathways, because it results in the activation of protein kinases that can phosphorylate key proteins required for cellular responses

The “arachidonic acid cascade” is activated in inflammation responses; “cox inhibitors” block cyclooxygenase

Not all responses to hydrophilic signals are immediate: Increases in gene expression can occur, and the resulting proteins can increase the target cells’ response

Eicosanoid: A lipid mediator of inflammation derived from the 20-carbon atom arachidonic acid (20 in Greek is "eicosa") or a similar fatty acid. The eicosanoids include the prostaglandins, prostacyclin, thromboxane, and leukotrienes.

 Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

Binding of the ligand to the receptor alters the receptor’s shape, which activates its enzyme function, phosphorylating an intracellular protein

(1) Tyrosine Kinase Receptor

Insulin receptor

Growth factor receptor

Mitogen-activated protein kinase (MAPK) pathway PTK: protein tyrosine kinasePTK: protein tyrosine kinase Ras: G protein. It consists of an  subunit,  subunit, and  subunitRas: G protein. It consists of an  subunit,  subunit, and  subunit MAPKKK: MAPK kinase kinaseMAPKKK: MAPK kinase kinase MAPKK: MAPK kinaseMAPKK: MAPK kinase MKP: MAPK phosphatasesMKP: MAPK phosphatases TF: tissue factorTF: tissue factor

(2) Receptor-associated tyrosine kinase JAK stands for Janus kinase or Just Another Kinase JAK2=Tyrosine protein kinase 2

Binding of the ligand to the receptor alters the receptor’s shape, which activates an associated enzyme function, phosphorylating an intracellular protein

(3) Receptor guanylyl cyclase Soluble GC

 Mediated by G protein-linked receptor  Mediated by enzyme-linked receptor  Mediated by ion channel Transmembrane signal transduction

Binding of the ligand to the receptor alters the receptor’s shape, which then opens (or closes) an ion channel

N 2 -ACh receptor channel

Any other pathway else? ? ?

Pheromone  Pheromones are chemicals emitted by living organisms to send messages to individuals of the same species.

The male silk moth bombyx mori (Fig. 1, left) can detect very low quantities of the sex pheromone bombykol emitted by the female, and at the same time distinguishes bombykol from many other, often similar, volatile compounds in the air. A first step of olfaction is the tranfer of bombykol to the pheromone receptor at the neuronal membrane via the pheromone-binding protein (BmorPBP). Highly efficient uptake and release kinetics of bombykol at the pheromone binding protein is essential for olfactory function. However, BmorPBP features a central hydrophobic binding cavity for bombykol, completely encapsulating the ligand (Fig. 1, right) and the exit/entrance gate for bombykol is not known. Yet, the ligand has to enter and exit the cavity fast and reversibly.

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