02.07.11Lecture 9:

Cell Communication I

Multicellular organisms need to coordinate cellular functions in different tissues

Cell-to-cell communication is also used by single celled organisms to signal to other organisms

Biologists have discovered several universal mechanisms of cellular regulation

General mechanism of cellular signaling

1. Reception of signal

2. Transduction of signal

3. Cellular response

Signal transduction

• Conversion of information from one form into another

Signaling cascades perform 5 crucial functions

1. Transduce signal into molecular form that can stimulate response

2. Relay signal from point of reception to point of action in the cell

3. Amplify the received signal4. Distribute the signal to

influence several responses in parallel

5. Each step is open to modulation by other signals

Receptors relay signals via intracellular signaling pathways

• Individual cells respond to a limited set of signals for which they have receptors

• A single cell may have 10 to 100,000 different receptors

• Many signals acting together can elicit different cellular responses - a complex network

A signaling molecule may induce different responses in different cell types

Extracellular signals can act slowly or rapidly

Signaling via chemical signals: direct communication

Signaling via chemical signals: local communication

Signaling via chemical signals: long-range communication

Extracellular signaling molecules fall into 2 classes:

1. Molecules that are small enough or hydrophobic and pass through the membrane - directly activate intracellular receptors in the cytoplasm or nucleus of target cell

2. Molecules that are too large or too hydrophilic to cross the plasma membrane - rely on membrane receptors

Nitric oxide (NO) signals through a cytoplasmic receptor

• NO is a chemically unstable gas

• NO is a small, uncharged molecule

Steroid hormones signal through intracellular receptors

• Steroid hormones are structurally similar to cholesterol

• Hydrophobic

Cell surface receptors fall into 3 main classes

1. Ion-channel-linked receptors

Convert chemical signals ==> electrical signals

2. G-protein-coupled receptors

• Largest family of cell surface receptors

• 7 transmembrane α-helices

• Extracellular N-term, intracellular C-term

• C-terminus interacts with downstream effectors

Many signaling proteins act as molecular “switches”

G proteins dissociate into 2 signaling complexes when activated

1. Signal molecule binds GPCR

2. Activated GPCR induces exchange of GDP for GTP on Gα subunit

3. Gα dissociates from Gβγ

4. Activated subunits diffuse within the plane of the membrane to activate downstream signaling molecules

The Gα subunit inactivates itself by hydrolyzing its GTP

G proteins regulate 2 types of targets

1. Ion channel opening (I.e. K+channels in heart muscle cells)

2. Membrane-bound enzymes (e.g. adenylyl cyclase, phospholipases)

Some G proteins regulate ion channels

• Acetylcholine slows the heart

• Receptor activation ==> dissociation of Gα and Gβγ

• Gβγ opens K+ channels to decrease the amplitude of contraction

Some G proteins regulate membrane-bound enzymes to make second

messengers

Two most common enzymes activated by G proteins

• Adenylyl cyclase - converts ATP into cyclic AMP (cAMP)

• Phospholipase C - cleaves a lipid (isositol phospholipid) into isositol-1,4,5-trisphosphate (IP3, a hydrophilic sugar) and diacylglycerol

(DAG, a lipid in the membrane)

Cyclic AMP (cAMP) is a common second messenger

• cAMP is generated from ATP by adenylyl cyclase

• cAMP is degraded by cAMP phosphodiesterase

• Caffeine inhibits phosphodiesterase

• cAMP activates cAMP-dependent protein kinase (PKA)

The activation of cyclic-AMP -dependent protein kinase (PKA)

Intracellular cAMP can activate gene transcription

Calcium ion concentrations are kept low in the cytosol by calcium pumps

Phospholipase C activates 2 signaling pathways