Lecture 19 - Cell Signaling

Cell-Cell communication

• Signaling cells release signaling molecules

• Receptors on or in the responding cell bind the signaling molecule

• Conformational change in the receptor changes

• The “signal is often transduced from one protein to another

• Response: the activity of the target cell changes

• Termination: signaling is terminated

Categories of short range signaling

• Paracrine signaling

• Juxtacrine signaling

• Autocrine signaling

Short-Range Signaling

• important during development and for tissue maintenance and are characteristic of all cell types

Categories of long-range signaling

• Electric Signaling

• Endocrine Signlaing

Electric Signaling

• along exons of nerve cells is essential for nervous systems to function

Endocrine Signaling

• essential for physiology and homeostasis (maintaining constant internal environment)

Signlaing Molecules and Receptors

• Two general categories:

  • Small Hydrophobic Signals

  • Large Hydrophobic Signals

Small Hydrophobic Signals

• lipid soluble and molecule can cross the plasma membrane to enter the cell

Large Hydrophobic Signals

• Lipid-insoluble and they cannot cross plasma membrane

Receptor Types

• Intracellular Receptors: Steroid Hormone Receptor

• Cell Surface Receptors: Ligand gated ion channels, g-protein couples receptors, receptor tyrosine kinases

What determines whether a cell responds to a signal

• A cell that expresses the receptor will respond, and a cell that does not express the receptor will not respond

What determines how a cell responds to the signal

• depends on the type of proteins present in the responding cell

Steroid Hormone Release

• Steroid hormones are lipids

• Binding proteins transport the hormone through the blood stream

Steroid hormone binds the receptor

• steroid hormone diffuses across the plasma membrane and binds intracellular receptor in the responding cell

• receptor changes conformation and the receptor + hormone enter the nucleus

Steroid Hormone receptor in the nucleus

• steroid hormone receptors are regulatory transcription factors

• in the nucleus, SHR bind to enhances to regulate transcription

Ligated Gated Ion Channels

• Ligand binding opens channel

• Ions move along concentration gradient

G Protein-coupled receptor signaling

GTP and ATP

• both are high free energy molecules

• energy is released when ATP or GTP is hydrolyzed

• GTP has guanine, ATP has adenine

Step 1 in Signaling Pathway

• signal arrives and binds receptor

Step 2 in Signaling Pathway

• Receptor changes conformation and binds G protein. G-protein replaces GDP with GTP

Step 3 in Signaling Pathway

• Active G-protein binds to and activates effector protein. Effector produces secondary messengers and triggers response

Second Messengers: Inside the cell

• G-protein-activated enzymes catalyze the production of many small nonprotein signaling molecules called second messengers that diffuse rapidly and spread the signal message throughout the cell

Termination pf G protein-coupled signaling

• Signaling molecule detaches. Receptor is inactivated

• G-protein hydrolyzes GTP to GDP and is inactivated

• Secondary messengers are degraded

Receptor tyrosine kinases

• signal arrives and binds receptor

• receptor dimerizes and is phosphorylated

• binds RAS, which makes GTP

GTP-bound RAS triggers a kinase cascade

• A phosphorylation cascades results from RAS activating a kinase, with each protein phosphorylating another until response is triggered

T

Termination of receptor tyrosine kinase signaling

• Phosphorylated proteins must be dephosphorylated by phosphatases

• Signlaing molecule detaches. Receptor is inactivated

• RAS hydrolyzes GTP to GDP and is inactivated

Autophosphorylation

• receptor phosphorylates itself

Similarities between Kinase Signaling and G-protein signaling

• they use either ATP or GTP

Differences b/w Kinase Signaling and G-protein signaling

Kinase Signaling:

• change in protein conformation by covalent addition of a phosphate

• addition of a non-hydrolyzable form of ATP inhibits signaling

G-Protein Signaling:

• change in protein conformation by non-covalent binding of GTP

• addition of a non-hydrolyzable form of GTP activates signaling