Cell Communication-I Pin Ling ( 凌 斌 ), Ph.D. Department of Microbiology & Immunology, NCKU ext 5632; Reference: “Mechanisms of Cell Communication”, The Cell (5th edition), Chapter 15

Outline General principles of cell communication Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators Signaling through enzyme-coupled cell-surface receptors Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins Signaling in plants Your involvement is the key to success in this lecture.

Features of Cell Communication 1.A single host cell (E. Coli) or multicellular organisms need to communicate with environmental cues (stimuli), then leading to appropriate responses. 2.How to do “Communication” with environmental cues? => Signaling Transduction

What is Signaling Transduction? Conversion of a signal from one physical or chemical form into another. The process initiated by recognition a Signal by a Sensor (receptor, kinase or enzyme) in the cell, then converting to one or more cellular responses through a series of signal transmission.

Inputs Responses Signals Cellular Responses (Proliferation, Differentiation, & Apoptosis) Signaling Cascades Cell Signaling Transduction Regulates Cellular Responses Human

Receptors Signal Transducers Effectors A simple scheme of signal transduction Molecules involved in this process, called Signaling Molecules

Figure 15-2 Molecular Biology of the Cell (© Garland Science 2008) Budding yeast cells responding to a mating factor (Pheromone) Budding yeast

Features of Cell Communication-I 1.Signal molecules bind to surface or intracellular receptors. 2.There are four types of cellular signaling: (1) Cell contact, (2) Paracrine, (3) Synaptic, and (4) Endocrine. 3.Extracellular signal molecules can act over short or long distance. 4. Extracellular signals can act slowly or rapidly to change the behavior of a target cell.

Cell surface vs intracellular receptors

Four types of intercellular signaling

Signaling via gap junctions

Strategies for long-range signaling

Early vs later responses to extracellular signals

Features of Cell Communication-II 1. Each cell is programmed to respond to the combinations of extracellular signal molecules. 2.Different cell types respond differently to the same extracellular signal molecules. 3.The same cell type can act differently depending upon signal concentration. 4.Examples of intracellular signaling, e.g. NO signaling, Nuclear receptor signaling.

Combinations of total signals decide the cell fate

Various cellular responses induced by acetylcholine

The same cell type can act differently upon signal concentration

NO functions in smooth muscle relaxation

Steroid hormones & other non- gaseous signal molecules

The Nuclear Receptor Family

Activation of nuclear receptors by ligand binding

Primary & secondary responses by nuclear receptors

Outline General principles of cell communication Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators Signaling through enzyme-coupled cell-surface receptors Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins Signaling in plants

Three classes of cell surface receptors

Features of intracellular signaling pathways-I 1.Small intracellular signaling molecules => 2 nd messengers, e.g. Ca2+, cAMP, or Diacylglycerol (DAG). 2. Large intracellular signaling molecules => Signaling proteins 3. Signaling proteins act as “Molecular Switches” regulated by post-translational modifications (PTMs). 4. Signaling complex formation enhances the efficiency & specificity of the response. 5. Modular interaction domains mediate interactions between signaling proteins

A Signaling cascade: A surface receptor to the nucleus

Molecular Switches: Post-Translational Modifications

Signal Integration

Signaling complex formation by a scaffold protein

Signaling complex formation by an activated receptor

Signaling complex formation on phosphoinositoide docking sites

Signaling complex formation using modular interaction domains

Features of intracellular signaling pathways-II 1.Cells can respond abruptly or gradually to an increasing signal. 2.Intracellular signaling networks use feedback loops to regulate the process. 3.Cells can adjust their sensitivity to a signal.

Smoothly graded vs switchlike signaling responses-I

Smoothly graded vs switchlike signaling responses-II

Activation curves for an allosteric protein by various effector concentrations

A positive vs negative feedback loop

Positive vs negative feedback loop

An example of a positive feedback loop

Many ways to become desensitized (adapted) to a signal

Outline General principles of cell communication Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators Signaling through enzyme-coupled cell-surface receptors Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins Signaling in plants

Signaling through G-protein-coupled cell surface receptors (GPCRs)-I 1.GPCRs are the largest family of cell-surface receptors (700 GRCRs in human). They mediate our sense of sight, smell, and taste. 2.Extracellular signaling molecules acting on GPCRs are varied in structure, including hormones, lipid mediators, & neurotransmitters. 3. All GPCRs have a common structure- a seven transmembrane peptide 4.All GPCRs use G proteins to relay the signal into the cell.

Signaling through G-protein-coupled cell surface receptors (GPCRs)-II 5.Some G proteins regulate the production of cyclic AMP. 6.Some G proteins activate an inosital phospholipid signaling pathway via Phospholipase C-beta (PLC-b).

GPCRs and G Protein GPCR G Protein:  subunit: GTPase  subunit &  subunit

Activation of GPCRs & G Protein

cAMP links some GPCR signals to gene expression

Some hormones act GPCR via cAMP

Activation of cAMP-dep protein kinase (PKA)

Some GPCRs activate PKC and cytosolic Ca 2+

Ca 2+ -mediated intracellular Signaling 1. Ca2+ functions as an intracellular mediator. 2.Ca2+ enter the cytosol from outside through various Ca2+ ion channel. 3.Ca2+ from the ER enter the cytosol through IP3 receptors or ryanodine receptors. 4.Several mechanisms keep Ca2+ in the cytosol low in resting cells. 5.Ca2+ oscillations affect a cell response. 6.Ca2+/Calmodulin-dep protein kinase mediate cellular responses (learning & memory in the nervous system).

Ca2+ functions as an intracellular mediator

Multiple ways to keep Ca2+ low in the cytosol

Vasopressin-induced Ca2+ oscillations in a liver cell Vasopressin GPCR PLC-  Ca2+ oscillations

Activation of CaM-kinase II

CaM-kinase II as a frequency decoder of Ca2+ oscillations

Smell &vision depend on GPCRs

A rod photoreceptor cell & its response to light

A rod photoreceptor cell & its response to light

Four major families of trimeric G proteins

GPCR desensitization depends on receptor phosphorylation

“Cell Communication II” to be continued

Figure Molecular Biology of the Cell (© Garland Science 2008)